Heterocyclic compounds

FIELD: chemistry.

SUBSTANCE: invention relates to new compounds of formula I. In general formula I A is C or N; B, D and E independently represent CR4, NR5, N, O or S; and a ring containing groups A, B, D, E, selected from thienyl, furan, imidazole, oxazole, isothiazole, thiazole, pyrrol, pyrazole; provided that: b) when A is N, not any of B, D, E can be O or S; and c) when A is C, B is CR4 and one of D or E is N or NR5, when any of D or E cannot be NR5 or N; G is N or C; R1 represents one or more substitutes selected from H, Ra halogen, -OH and -ORa; R2 represents one or more substitutes selected from H, halogen and C1-6-alkyl, and also one of substitutes R2 can be -ORb' , -NRb' Rb', -SRb', -SORb', -SO2Rb', -SO2NRb' Rb'; R3 is H, or Cy, selected from phenyl optionally substituted with one or more substitutes selected from Rc , where Rc independently represents halogen, -ORg', where Rg' independently represents a Rg group, where Rg is C1-6-alkyl; each R4 independently represents H, Re, halogen, -CORe', -CO2Re', -CONRe'Re', -NRe'Re'; R5 independently represents H, Re, -CORe, -CONReRe, -SORe or -SO2Re; each Ra independently represents C1-6-alkyl or halogen- C1-6-alkyl; each R independently represents C1-6-alkyl optionally substituted with one or more substitutes selected from Rd and Rf; each Rb' independently represents H or Rb; each Rc independently represents halogen, -ORg', -CONRg'Rg', -NRg'Rg'; Rd is Cy optionally substituted with one or more Rf substitutes; each Rc independently represents C1-6-alkyl optionally substituted with one or more substitutes selected from Rc and Cy*, or Re is Cy, where any of the groups Cy or Cy* can optionally be substituted with one or more substitutes selected from Rc and Rg ; each Re' independently represents H or Re; each Rf independently represents a halogen, -ORh', -CO2Rh; each Rg independently represents Rd or C1-6-alkyl optionally substituted with one or more substitutes selected from Rd and Rf; each Rg' independently represents H or Rg; each Rh independently represents C1-6-alkyl, halogen-C1-6-alkyl or hydroxy- C1-6-alkyl; each Rh' independently represents H or Rh; and Cy or Cy* given in definitions above is a partially saturated, saturated or aromatic 3-7-member monocyclic carbocyclic ring which optionally contains 1-2 heteroatoms selected from N and O, and where the ring or rings can be bonded to the remaining part of the molecule through a carbon or nitrogen atom.

EFFECT: obtaining formula I compounds with p38-kinase inhibitory properties which can be used in making drugs for treating such diseases as tumour immune and autoimmune diseases etc.

21 cl, 10 dwg, 8 tbl, 57 ex

 

The present invention relates to a new group of heterocyclic compounds, and method of production thereof, to pharmaceutical compositions containing such compounds and to their use in therapy.

Kinases are proteins involved in different cellular responses to external signals. In the nineties it was revealed a new family of kinases, named MARK (mitogenactivated protein kinase). MARK activate their substrates by phosphorylation of serine and treoninove residues.

MARK activated by other kinases in response to a wide range of signals, including growth factors, proinflammatory cytokines, UV radiation, endotoxins and osmotic stress. As soon as they are activated, MARC by phosphorylation activates other kinases or proteins, such as transcription factors, which ultimately cause an increase or decrease in the expression of a specific gene or group of genes.

The family of MARK includes kinases, such as p38, ERK (extracellular regulated protein kinase) and JNK (C-Jun N-terminal kinase).

p38-Kinase plays a key role in the cellular response to stress and ways of activation in the synthesis of numerous cytokines, in particular tumor necrosis factor (TNF-α), interleukin-1 (IL-1), interleukin-6 (IL-6) and interleukin-8 (IL-8).

IL-1 and TNF-α are produced by macrophages and and monocytes and is involved in mediating an immunoregulatory processes and other physiopathological States. For example, elevated levels of TNF-α is associated with inflammatory and autoimmune diseases and processes that trigger the degradation of connective and bone tissue, such as rheumatoid arthritis, osteoarthritis, diabetes, inflammatory bowel disease and sepsis.

Thus, it is believed that for the treatment or prevention of diseases, such as the above-mentioned diseases, mediated by cytokines, such as IL-1 and TNF-α, can be applied inhibitors of p38 kinase.

On the other hand, it was also found that the p38 inhibitors inhibit other Pro-inflammatory proteins such as IL-6, IL-8, interferon-γ and GM-CSF (colony stimulating factor granulocyte-macrophage). In addition, in recent studies it was found that p38 inhibitors block not only the synthesis of cytokines, but also a cascade of signals that they induce, such as the induction of the enzyme cyclooxygenase-2 (COX-2).

On this basis, it would be desirable to obtain new compounds that are able to inhibit p38-kinase.

One aspect of the present invention relates to new compounds of General formulaI

in which

A represents C or N;

B, D and E independently represent CR4, NR5, N, O, or S

the following conditions are met:

a) when one of B, D or E represents the FDS is th O or S, the other two cannot represent O or S;

b) when A represents N, none of B, D, E cannot represent O or S; and

(C) when A is C, b is a CR4and one of D or E is N or NR5while the other from D or E to represent NR5or N;

G represents N or C;

R1represents one or more substituents selected from H, Ra, halogen, -CN, -OH and-or SIGa;

R2represents one or more substituents selected from H, halogen and C1-6-alkyl, and, in addition, one of the substituents R2may also represent-ORb', -NO2, -CN, -fulfills I TS corb', -CO2Rb', -CONRb'Rb', -NRb'Rb', -NRb'CORb', -NRb'CONRb'Rb', -NRb'CO2Rb, -NRb'SO2Rb, -SRb', -SORb, -SO2Rb, -SO2NRb'Rb'or C1-6-alkyl, optionally substituted by one or more substituents Rc;

R3represents a

H, C1-6-alkyl, optionally substituted by one or more substituents selected from Rcand Rdor

Cy, optionally substituted by one or more substituents selected from Rc, Rdand C1-6-alkyl, long is correctly substituted by one or more substituents, selected from Rcand Rd;

each R4independently represents H, Re, halogen, -ORe', -NO2, -CN, -CORe', -CO2Re', -CONRe'Re', -NRe'Re', -NRe'CORe', -NRe'CONRe'Re', -NRe'CO2Re, -NRe'SO2Re, -SRe', -SORe, -SO2Reor SO2NRe'Re';

R5independently represents H, Re, -CORe, -CONReRe, -SOReor-SO2Re;

each Raindependently represents a C1-6-alkyl or halogen-C1-6-alkyl;

each Rbindependently represents a C1-6-alkyl or Cywhere both groups optionally can be substituted by one or more substituents selected from Rdand Rf;

each Rb'independently represents H or Rb;

each Rcindependently represents halogen, -ORg', -NO2, -CN, -CORg', -CO2Rg', -CONRg'Rg', -NRg'Rg', -NRg'CORg', -NRg'CONRg'Rg', -NRg'CO2Rg, -NRg'SO2Rg, -SRg', -SORg, -SO2Rgor-SO2NRg'Rg';

Rdrepresents a Cy, optionally substituted by one or more substituents Rf;

<> each Reindependently represents a C1-6-alkyl, optionally substituted by one or more substituents selected from Rcand Cy*or Rerepresents a Cywhere any of the groups Cyor Cy* optionally can be substituted by one or more substituents selected from Rcand Rg;

each Re'independently represents H or Re;

each Rfindependently represents halogen, Rh, -Or SIGh', -NO2, -CN, -CORh', -CO2Rh', -CONRh'Rh', -NRh'Rh', -NRh'CORh', -NRh'CONRh'Rh', -NRh'CO2Rh, -NRh'SO2Rh, -SRh', -SORh, -SO2Rhor-SO2NRh'Rh';

each Rgindependently represents Rdor C1-6-alkyl, optionally substituted by one or more substituents selected from Rdand Rf;

each Rg'independently represents H or Rg;

each Rhindependently represents a C1-6-alkyl, or halogen-C1-6-alkyl or hydroxy-C1-6-alkyl;

each Rh'independently represents H or Rhand

Cyor Cy* in the above definitions represents a partially unsaturated, saturated with the second or aromatic 3-7 membered monocyclic or 8-12 membered bicyclic carbocyclic ring, which optionally contains from 1 to 4 heteroatoms selected from N, S and O, where one or more atoms of C, N or S optionally can be oxidized forming CO, N+O-SO or SO2respectively, and where the specified ring or rings may be connected with the rest of the molecule through a carbon atom or a nitrogen atom.

The present invention also relates to salts and solvate of the compound of the formulaI.

Some compounds of the formulaImay contain chiral centers, which may lead to different stereoisomers. The present invention relates to all stereoisomers and their mixtures.

Compounds of the formulaIare inhibitors of p38 kinase and also inhibit the formation of cytokines, such as TNF-α.

Thus, another aspect of the invention relates to the compound of General formulaI

in which

A represents C or N;

B, D and E independently represent CR4, NR5, N, O, or S

the following conditions are met:

a) when one of B, D or E represents O or S, the other two cannot represent O or S;

b) when A represents N, none of B, D, E cannot represent O or S; and

c) when A is C, B is CR4and one of D or E is N or NR5, then who and how the other from D or E to represent NR 5or N;

G represents N or C;

R1represents one or more substituents selected from H, Ra, halogen, -CN, -OH and-or SIGa;

R2represents one or more substituents selected from H, halogen and C1-6-alkyl, and, in addition, one substituent R2may also represent-or SIGb', -NO2, -CN, -CORb', -CO2Rb', -CONRb'Rb', -NRb'Rb', -NRb'CORb', -NRb'CONRb'Rb', -NRb'CO2Rb, -NRb'SO2Rb, -SRb', -SORb, -SO2Rb, -SO2NRb'Rb'or C1-6-alkyl, optionally substituted by one or more substituents Rc;

R3represents a

H, C1-6-alkyl, optionally substituted by one or more substituents selected from Rcand Rdor

Cy, optionally substituted by one or more substituents selected from Rc, Rdand C1-6-alkyl, optionally substituted by one or more substituents selected from Rcand Rd;

each R4independently represents H, Re, halogen, -ORe', -NO2, -CN, -CORe', -CO2Re', -CONRe'Re', -NRe'Re', -NRe'CORe', -NRe'CNRe'Re' , -NRe'CO2Re, -NRe'SO2Re, -SRe', -SORe, -SO2Reor-SO2NRe'Re';

R5independently represents H, Re, -CORe, -CONReRe, -SOReor-SO2Re;

each Raindependently represents a C1-6-alkyl or halogen-C1-6-alkyl;

each Rbindependently represents a C1-6-alkyl or Cywhere both groups optionally can be substituted by one or more substituents selected from Rdand Rf;

each Rb'independently represents H or Rb;

each Rcindependently represents halogen, -ORg', -NO2, -CN, -CORg', -CO2Rg', -CONRg'Rg', -NRg'Rg', -NRg'CORg', -NRg'CONRg'Rg', -NRg'CO2Rg, -NRg'SO2Rg, -SRg', -SORg, -SO2Rgor-SO2NRg'Rg';

Rdrepresents a Cy, optionally substituted by one or more substituents Rf;

each Reindependently represents a C1-6-alkyl, optionally substituted by one or more substituents selected from Rcand Cy*or Rerepresents a Cywhere any of the groups Cyor Cy* optionally can be substituted by one or more substituents, selected from Rcand Rg;

each Re'independently represents H or Re;

each Rfindependently represents halogen, Rh, -ORh', -NO2, -CN, -CORh', -CO2Rh', -CONRh'Rh', -NRh'Rh', -NRh'CORh', -NRh'CONRh'Rh', -NRh'CO2Rh, -NRh'SO2Rh, -SRh'-The separator R s oh, -SO2Rhor-SO2NRh'Rh';

each Rgindependently represents Rdor C1-6-alkyl, optionally substituted by one or more substituents selected from Rdand Rf;

each Rg'independently represents H or Rg;

each Rhindependently represents a C1-6-alkyl, halogen-(C1-6-alkyl or hydroxy-C1-6-alkyl;

each Rh'independently represents H or Rh; and

Cyor Cy* in the above definitions represents a partially unsaturated, saturated or aromatic 3-7 membered monocyclic or 8-12 membered bicyclic carbocyclic ring, which optionally contains 1 to 4 heteroatoms selected from N, S and O, where one or more atoms of C, N or S optionally can be oxidized forming CO, N+O-SO or SO2respectively, and where asanee ring or rings may be connected with the rest of the molecule through a carbon atom or a nitrogen atom,

for use in therapy.

Another aspect of the present invention relates to a pharmaceutical composition which contains a compound of the formulaIor its pharmaceutically acceptable salt and one or more pharmaceutically acceptable excipients.

Another aspect of the present invention relates to the use of compounds of the formulaIor its pharmaceutically acceptable salt for the manufacture of a medicinal product for the treatment or prevention of diseases mediated by p38.

Another aspect of the present invention relates to the use of compounds of the formulaIor its pharmaceutically acceptable salt for the manufacture of a medicinal product for the treatment or prevention of diseases mediated by cytokines.

Another aspect of the present invention relates to the use of compounds of the formulaIor its pharmaceutically acceptable salt for the manufacture of a medicinal product for the treatment or prevention of diseases mediated by TNF-α, IL-1, IL-6 and/or IL-8.

Another aspect of the present invention relates to the use of compounds of the formulaIor its pharmaceutically acceptable salt for the manufacture of a medicinal product for the treatment or prevention of a disease selected from immune, autoimmune and inflammatory diseases, cardiovascular for the of olivani, infectious diseases, diseases associated with bone resorption, neurodegenerative diseases, proliferative diseases and processes associated with the induction of cyclooxygenase-2.

Another aspect of the present invention relates to the use of compounds of the formulaIor its pharmaceutically acceptable salts for the treatment or prevention of diseases mediated by p38.

Another aspect of the present invention relates to the use of compounds of the formulaIor its pharmaceutically acceptable salts for the treatment or prevention of diseases mediated by cytokines.

Another aspect of the present invention relates to the use of compounds of the formulaIor its pharmaceutically acceptable salts for the treatment or prevention of diseases mediated by TNF-α, IL-1, IL-6 and/or IL-8.

Another aspect of the present invention relates to the use of compounds of the formulaIor its pharmaceutically acceptable salts for the treatment or prevention of a disease selected from immune, autoimmune and inflammatory diseases, cardiovascular diseases, infectious diseases, diseases associated with bone resorption, neurodegenerative diseases, proliferative diseases and processes associated with the induction of cyclooxygenase-2.

Another aspect of this is bretania relates to a method of treatment or prevention of disease, mediated p38, the subject in need of such treatment, in particular in humans, which includes the introduction of a specified subject a therapeutically effective amount of the compounds of formulaIor its pharmaceutically acceptable salt.

Another aspect of the present invention relates to a method of treatment or prevention of diseases mediated by cytokines, the subject in need of such treatment, in particular in humans, which includes the introduction of a specified subject a therapeutically effective amount of the compounds of formulaIor its pharmaceutically acceptable salt.

Another aspect of the present invention relates to a method of treatment or prevention of diseases mediated by TNF-α, IL-1, IL-6 and/or IL-8 in a subject in need of such treatment, in particular in humans, which includes the introduction of a specified subject a therapeutically effective amount of the compounds of formulaIor its pharmaceutically acceptable salt.

Another aspect of the present invention relates to a method of treatment or prophylaxis of a disease selected from immune, autoimmune and inflammatory diseases, cardiovascular diseases, infectious diseases, diseases associated with bone resorption, neurodegenerative diseases, proliferative diseases and processes, the Association is aligned with the induction of cyclooxygenase-2, the subject in need of such treatment, in particular in humans, which includes the introduction of a specified subject a therapeutically effective amount of the compounds of formulaIor its pharmaceutically acceptable salt.

Another aspect of the present invention relates to a method for obtaining compounds of the formulaIthat includes

(a) when in the compound of the formulaIA represents C, the interaction of the ketone of the formulaIV

in which G, R1and R2have the meanings described for the General formulaIwith a heterocyclic amine of the formulaIIIand the aldehyde of the formulaII

in which B, D, E, and R3have the meanings described for the General formulaI; or

(b) when in the compound of the formulaIA represents N and R3is a group identical to phenyl, substituted R1located at the adjacent position relative to the N atom in the 6-membered ring Central bicyclic fragment, the interaction of the compounds of formulaXXII

in which G, R1and R2have the meanings described for the General formulaIwith a heterocyclic amine of the formulaXXIII

in which B, D and E have the meanings described for the General formulaI; or

I; and

(d) if required, after any of the above stages a, b or c the interaction of the compounds of formulaIwith base or acid to obtain the corresponding salt.

Another aspect of the present invention relates to a method for obtaining compounds of formula

which includes interaction propenone formula

in which G, R1and R2have the previously indicated meanings, with a heterocyclic amine of the formula

in which B, D and E independently represent CR4, NR5, N, O, or S; provided that when one of B, D or E represents O or S, the other two cannot represent O or S; and R4and R5have these values.

In the definitions of the present invention, the term "C1-6-alkyl" as a group or part of a group means alkyl straight or branched chain, containing from 1 to 6 carbon atoms. Examples of other groups include methyl, ethyl, sawn, ISO-propyl, butylene, isobutylene, second-butylene, tert-butylene, Pintilie, isopentyl, neopentyl and hexylene group.

Halogen-C1-6is an alkyl group means a group obtained by substituting one or more hydrogen atoms in the C1-6-alkylen the first group by one or more halogen atoms (i.e. the fluorine, chlorine, bromine or iodine), which may be the same or different. Examples, among other groups, include triptoreline, formeterol, 1-chloraniline, 2-chloraniline, 1-foretelling, 2-foretelling, 2-bromatology, 2-togethernow, 2,2,2-triptoreline, pentatration, 3-forproperty, 3-chloropropylene, 2,2,3,3-tetrafluoropropyl, 2,2,3,3,3-pentafluoropropanol, heptafluoropropyl, 4-terbutaline, nonafterburning, 5-forinternal and 6-perhexiline group.

Hydroxy-C1-6is an alkyl group means a group obtained by substituting one or more hydrogen atoms in the C1-6is an alkyl group of one or more-OH groups. Examples, among other groups, include hydroxymethylene, 1-hydroxyethylene, 2-hydroxyethylene, 1,2-dihydroxyethyl, 3-hydroxypropyl, 4-hydroxybutyl, 5-hydroxypentanal and 6-hydroxyhexyloxy group.

Radical halogen means fluorine, chlorine, bromine or iodine.

The terms "Cy" or "Cy*" as a group or part of a group refers to a 3-7-membered monocyclic or 8-12 membered bicyclic carbocyclic group, which may be partially unsaturated, saturated or aromatic, which optionally contains 1 to 4 heteroatoms selected from N, S and O, and in which the specified ring or rings may be associated with frequent rest is Yu molecule through a carbon atom or a nitrogen atom. When group Cyor Cy* is a saturated or partially unsaturated, one or more atoms of C or S atoms can be optionally oxidized forming group CO, SO or SO2. When group Cyor Cy* is aromatic, one or more N atoms optionally can be oxidized, forming a group of N+O-. Ring Cyor Cy* can be substituted as described in the definition of General formulaI; if the ring is substituted, the substituents can be the same or different and may be located in any suitable position. Group Cyor Cy* can be connected with the rest of the molecule via any suitable carbon atom or a nitrogen atom. Preferably the group Cyor Cy* represents a 3-7-membered monocyclic ring. Examples of groups Cyor Cy*among other groups, include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, aziridinyl, oxiranyl, oxetanyl, imidazolidinyl, isothiazolinones, isoxazolidine, oxazolidine, pyrazolidine, pyrrolidine, thiazolidine, dioxane, morpholinyl, piperazinil, piperidinyl, pyranyl, tetrahydropyranyl, azepine, oxazinyl, oxazolines, pyrrolines, thiazolyl, pyrazolyl, imidazolyl, isoxazolyl, isothiazolines, phenyl, naphthyl, 1,2,4-oxadiazolyl, 1,2,4-Tyagi who was Salil, 1,3,4-oxadiazolyl, 1,3,4-thiadiazolyl, furyl, imidazolyl, isoxazolyl, isothiazolin, oxazolyl, pyrazolyl, pyrrolyl, thiazolyl, thienyl, 1,2,3-triazolyl, 1,2,4-triazolyl, pyrazinyl, pyridazinyl, pyridinyl, pyrimidinyl, benzimidazolyl, benzofuranyl, isobenzofuranyl, benzothiazolyl, benzothiophene, isobenzofuranyl, imidazopyridines, imidazopyridines, imidazopyridines, imidazopyrimidines, indazoles, indolyl, isoindolyl, ethenolysis, tetrahydroisoquinoline, naphthyridine, pyrazolopyrimidines, pyrazolopyrimidines, pyrazolopyrimidines, purinol, hintline, chinoline, honokalani, cyclobutanone, Cyclopentanone, cyclohexanone, cycloheptanone, 2-oxopyrrolidin, 2-oxopiperidine, 4-oxopiperidine, 2(1N)-pyridinyl, 2(1H)-pyrazinyl, 2(1N)-pyrimidinone, 2(1H)-pyridazinone and phthalimides.

The term "heteroaryl" means an aromatic 5 - or 6-membered monocyclic ring or a 8-12 membered bicyclic ring, which contains 1 to 4 heteroatoms selected from N, S and O. the N Atoms in the ring optionally can be oxidized, forming N+O-. Heteroaryl group may be connected with the rest of the molecule via any suitable carbon atom or a nitrogen atom. Heteroaryl group optionally can be substituted as described whenever used such a term; if it gets rohilla group substituted, the substituents can be the same or different and may be located in any suitable position in the ring. Preferably the heteroaryl group is a 5 - or 6-membered monocyclic ring. Examples of heteroaryl groups, among other groups, include 1,2,4-oxadiazolyl, 1,2,4-thiadiazolyl, 1,3,4-oxadiazolyl, 1,3,4-thiadiazolyl, furyl, imidazolyl, isoxazolyl, isothiazolin, oxazolyl, pyrazolyl, pyrrolyl, thiazolyl, thienyl, 1,2,3-triazolyl, 1,2,4-triazolyl, pyrazinyl, pyridazinyl, pyridinyl, pyrimidinyl, benzimidazolyl, benzofuranyl, benzothiazolyl, benzothiophene, imidazopyridines, imidazopyridines, imidazopyridines, imidazopyrimidines, indazoles, indolyl, isoindolyl, ethenolysis, naphthyridine, pyrazolopyrimidines, pyrazolopyrimidines, pyrazolopyrimidines, purinol, hintline, chinoline and honokalani.

Definitions heteroaryl Cyand Cy*when in General terms the specific examples relate to the bicyclic ring included all possible locations of the atoms. Thus, for example, the term "pyrazolopyrimidines" may include groups such as 1H-pyrazolo[3,4-b]pyridinyl, pyrazolo[1,5-a]pyridinyl, 1H-pyrazolo[3,4-c]pyridinyl, 1N-pyrazolo[4,3-c]pyridinyl, and 1H-pyrazolo[4,3-b]pyridinyl; the term "imidazopyridines" may include groups such as 1H-is imidazo[4,5- b]pyrazinyl, imidazo[1,2-a]pyrazinyl, imidazo[1,5-a]pyrazinyl, and the term "pyrazolopyrimidines" may include groups such as 1H-pyrazolo[3,4-d]pyrimidinyl, 1H-pyrazolo[4,3-d]pyrimidinyl, pyrazolo[1,5-a]pyrimidines and pyrazolo[1,5-c]pyrimidinyl.

The expression "optionally substituted one or more" means that the group may be substituted by one or more, preferably 1, 2, 3 or 4 substituents, provided that such a group contains 1, 2, 3 or 4 position, allowing the implementation of substitution.

In the definition of compounds of the formulaIthe Central bicyclic ring

represents an aromatic ring.

In the compound of the formulaIR1represents one or more, preferably one or two groups independently selected from H, Ra, halogen, -CN, -OH and-or SIGa. The group or groups R1can be located in any suitable position of the phenyl ring, and when there is more than one group R1they may be the same or different.

In the compound of the formulaIR2represents one or more, preferably one or two groups independently selected from H, halogen and C1-6-alkyl, and, in addition, one substituent R2may also represent-the R b', -NO2, -CN, -CORb', -CO2Rb', -CONRb'Rb', -NRb'Rb', -NRb'CORb', -NRb'CONRb'Rb', -NRb'CO2Rb, -NRb'SO2Rb, -SRb', -SORb, -SO2Rb, -SO2NRb'Rb'or C1-6-alkyl, optionally substituted by one or more substituents Rc. The group or groups R2can be located at any suitable carbon atom in the pyridine or pyrimidine ring, including G, when G is a C.

Thus, the invention relates to defined above for the compounds of the formulaI.

In yet another embodiment, the invention relates to compounds of the formulaIin which R1represents one or more substituents selected from H, Ra, halogen and-or SIGa.

In yet another embodiment, the invention relates to compounds of the formulaIin which R1represents one or more substituents selected from H, halogen, halogen-C1-6-alkyl and C1-6-alkoxy.

In yet another embodiment, the invention relates to compounds of the formulaIin which R1represents one or two substituent selected from halogen, halogen-C1-6-alkyl and C1-6-alkoxy.

In yet another variant is sushestvennee the invention relates to compounds of the formula Iin which R1represents one or more substituents selected from H, halogen and halogen-C1-6-alkyl.

In yet another embodiment, the invention relates to compounds of the formulaIin which R1represents one or more substituents selected from halogen (preferably fluorine) and the halogen-C1-6-alkyl (preferably CF3).

In an additional embodiment, the invention relates to compounds of the formulaIin which R1represents one or more halogen atoms.

In an additional embodiment, the invention relates to compounds of the formulaIin which R2represents one Deputy, selected from H, halogen, C1-6-alkyl, -ORb', -NRb'CORb'and-NRb'Rb'.

In an additional embodiment, the invention relates to compounds of the formulaIin which R2represents one Deputy, selected from H, halogen, C1-6-alkyl, -ORb'and-NRb'Rb'.

In an additional embodiment, the invention relates to compounds of the formulaIin which R2represents one Deputy, is selected from H and-NRb'Rb'.

In an additional embodiment, the invention relates to the soedinenijam formula Iin which G represents C and R2represents H.

In an additional embodiment, the invention relates to compounds of the formulaIin which G represents N and R2represents-NRb'Rb'and is in position 2 of the pyrimidine ring.

In an additional embodiment, the invention relates to compounds of the formulaIin which G represents N, R2is an-otherband is in position 2 of the pyrimidine ring and Rbrepresents a C1-6-alkyl, substituted by one Deputy, selected from Cyand-ORh'.

In an additional embodiment, the invention relates to compounds of the formulaIin which R3represents H or Cy, optionally substituted by one or more substituents selected from Rc, Rdand C1-6-alkyl, optionally substituted by one or more substituents selected from Rcand Rd.

In an additional embodiment, the invention relates to compounds of the formulaIin which R3represents H, heteroaryl or phenyl, in which heteroaryl and phenyl optionally can be substituted by one or more substituents selected from Rc, Rdand C1-6-alkyl, it is certainly substituted by one or more substituents, selected from Rcand Rd.

In an additional embodiment, the invention relates to compounds of the formulaIin which R3represents H, heteroaryl or phenyl, in which heteroaryl and phenyl optionally can be substituted by one or more halogen atoms.

In an additional embodiment, the invention relates to compounds of the formulaIin which R3represents H or phenyl, optionally substituted by one or more halogen atoms.

In an additional embodiment, the invention relates to compounds of the formulaIin which R3represents H.

In an additional embodiment, the invention relates to compounds of the formulaIin which R3represents a Cy, optionally substituted by one or more substituents selected from Rc, Rdand C1-6-alkyl, optionally substituted by one or more substituents selected from Rcand Rd.

In an additional embodiment, the invention relates to compounds of the formulaIin which R3is heteroaryl or phenyl, in which heteroaryl and phenyl optionally can be substituted by one or more substituents selected from Rc, Rdand C 1-6-alkyl, optionally substituted by one or more substituents selected from Rcand Rd.

In an additional embodiment, the invention relates to compounds of the formulaIin which R3is heteroaryl or phenyl, in which heteroaryl and phenyl optionally can be substituted by one or more halogen atoms.

In an additional embodiment, the invention relates to compounds of the formulaIin which R3represents phenyl, optionally substituted by one or more halogen atoms.

In an additional embodiment, the invention relates to compounds of the formulaIin which G represents C, R2represents H and R3is heteroaryl or phenyl, in which heteroaryl and phenyl optionally can be substituted by one or more substituents selected from Rc, Rdand C1-6-alkyl, optionally substituted by one or more substituents selected from Rcand Rd.

In an additional embodiment, the invention relates to compounds of the formulaIin which G represents C, R2represents H and R3is heteroaryl or phenyl, in which heteroaryl and phenyl optionally could the t to be substituted by one or more halogen atoms.

In an additional embodiment, the invention relates to compounds of the formulaIin which G represents C, R2represents H and R3represents phenyl, optionally substituted by one or more halogen atoms.

In an additional embodiment, the invention relates to compounds of the formulaIin which G represents N, R2represents-NRb'Rb'and is in position 2 of the pyrimidine ring and R3represents H.

In an additional embodiment, the invention relates to compounds of the formulaIin which G represents N, R2is an-otherband is in position 2 of the pyrimidine ring, Rbrepresents a C1-6-alkyl, substituted by one Deputy, selected from Cyand-ORh'and R3represents H.

In an additional embodiment, the invention relates to compounds of the formulaIin which R4independently represents H, Re, -CORe', -CO2Re', -CONRe'Re'or-NRe'Re'.

In an additional embodiment, the invention relates to compounds of the formulaIin which R4independently represents H, -CORe', -CONRe'Re'or C 1-6-alkyl, optionally substituted by one or more substituents selected from Rc.

In an additional embodiment, the invention relates to compounds of the formulaIin which R4independently represents H, -CORe', -CONRe'Re'C1-6-alkyl, hydroxy-C1-6-alkyl or-CH2NRg'Rg'.

In an additional embodiment, the invention relates to compounds of the formulaIin which R5represents H or Re.

In an additional embodiment, the invention relates to compounds of the formulaIin which R5represents H or C1-6-alkyl.

In an additional embodiment, the invention relates to compounds of the formulaIin which R5represents a C1-6-alkyl.

In an additional embodiment, the invention relates to compounds of the formulaIin which A is a C.

In an additional embodiment, the invention relates to compounds of the formulaIin which A represents n

In an additional embodiment, the invention relates to compounds of the formulaIin which

represents a group selected from (a)to(h)

In an additional embodiment, the invention relates to compounds of the formulaIin which

represents a group selected from (a)to(d)

In an additional embodiment, the invention relates to compounds of the formulaIin which

represents a group selected from (a)-(c)

In an additional embodiment, the invention relates to compounds of the formulaIin which A is C; B and D represent CR4and E is O.

In an additional embodiment, the invention relates to compounds of the formulaIin which A represents C; D and E represent CR4and B represents NR5.

In an additional embodiment, the invention relates to compounds of the formulaIin which A represents C; D represents CR4and one of B and E represents N and the other of B and E is NR5.

In an additional embodiment, the invention relates to compounds of the formulaIin which A represents C; D represents CR4E represents N and B represents NRsup> 5.

In an additional embodiment, the invention relates to compounds of the formulaIin which A is a C; E represents CR4D represents N and B represents NR5.

In all the above embodiments, the implementation of all groups that are not given a specific definition have the meanings previously defined in relation to compounds of the formulaI.

In addition, the present invention covers all possible combinations described above, a particular and preferred groups.

In an additional embodiment, the invention relates to compounds of the aforementioned formulaIthat provide more than 50%inhibition of p38 activity at 10 μm, more preferably at 1 μm and even more preferably at 0.1 μm, in the test p38, such as the test described in example 57.

Compounds of the present invention contain one or more basic nitrogen atoms and, hence, can form salts with organic or inorganic acids. Examples of such salts include salts with inorganic acids such as hydrochloric acid, Hydrobromic acid, uudistoodetena acid, nitric acid, Perlina acid, sulfuric acid or phosphoric acid; and salts with organic acids, t is Kimi as methanesulfonate acid, triftormetilfullerenov acid, econsultancy acid, benzolsulfonat acid, p-toluensulfonate acid, fumaric acid, oxalic acid, acetic acid, maleic acid, ascorbic acid, citric acid, lactic acid, tartaric acid, malonic acid, glycolic acid, succinic acid and propionic acid, among others. Some compounds of the present invention may contain one or more acidic protons and, therefore, they can also form salts with bases. Examples of such salts include salts with inorganic cations such as the cations of sodium, potassium, calcium, magnesium, lithium, aluminum, zinc, etc.; and salts formed with pharmaceutically acceptable amines such as ammonia, alkylamines followed, hydroxyethylamine, lysine, arginine, N-methylglucamine, procaine, etc.

There are no limitations on the type of salt that can be used, provided that such salts are pharmaceutically acceptable in their use for therapeutic purposes. The term "pharmaceutically acceptable salt" refers to those salts which, in accordance with the medical expertise suitable for use when coming in contact with the tissues of humans and other mammals without undue toxicity, irritation, allergic response and the like Pharmaceutically who ielemia salts are well known in this field.

Salts of compounds of the formulaIcan be obtained during the final isolation and purification of the compounds according to the invention or can be obtained by treating compounds of the formulaIa sufficient amount of the desired acid or base to obtain salts accepted way. Salts of compounds of the formulaIcan be converted into other salts of compounds of the formulaIusing ion exchange using an ion-exchange resin.

The compounds of formula I and their salts may differ in certain physical properties, although they are equivalent for the purposes of the present invention. All salts of the compounds of the formulaIincluded in the scope of the invention.

Compounds of the present invention can form complexes with solvents in which they are interacting or from which they are precipitated or crystallized. Such complexes are known as a solvate. Used here, the term "MES" refers to a complex of variable stoichiometry formed by the dissolved substance (compound of the formulaIor its salt and a solvent. Examples of solvents include pharmaceutically acceptable solvents such as water, ethanol and the like, a Complex of water known as the hydrate. The solvate of the compounds according to the invention (or their salts), including hydrates, included in the scope of the invention.

Some of the compounds according to present the invention can exist in several diastereoisomers and/or more optical isomers. Diastereoisomer you can select conventional methods such as chromatography or fractional crystallization. To obtain optically pure isomers optical isomers can be divided generally accepted methods of separation of optical isomers. Such a division can be made in respect of any chiral intermediates for the synthesis or products of General formulaI. Optically pure isomers can also be obtained individually, applying enantiospecific synthesis. The present invention encompasses all of the individual isomers, and mixtures thereof (e.g. racemic mixtures or mixtures of diastereoisomers), obtained either by synthesis or by physical blending.

Compounds of the formulaIcan be obtained using the following, the methods described below. As will be obvious to the person skilled in the art, the particular method used to obtain a particular connection may be critically dependent on its chemical structure. In addition, some of the following methods may be necessary or advisable to protect the reactive or labile group conventional protective groups. As the nature of such protective groups, and procedures for their introduction or removal are well known in the art (see, for example, the publication T.W. Greene and P.G.M Wuts, "Protective Groups in Organic Synthesis", John Wiley & Sons, 3-s from the W, 1999). For example, as protective groups for functional amino groups can be applied tert-butoxycarbonyl (Vos) or benzyl (Bn) group. The carboxyl group can be protected, for example, in the form of a complex C1-6-alilovic esters or complex arylalkyl esters, such as benzyl ether, while the hydroxyl group can be protected, for example, using tetrahydropyranyl (THP) groups. Whenever used protective group, you then need the stage of removing the protection that can be performed in standard conditions of organic synthesis, such as the conditions described in the above link.

If not made special reservations in the following ways values of various substituents are the values described above in relation to compounds of General formulaI.

In General, compounds of formulaIin which A represents C (i.e. the connectionIa), can be obtained by the interaction of the aldehyde of the formulaIIwith the heterocyclic amine of the formulaIIIand the compound of the formulaIVas shown in the following diagram:

where G, B, D, E, R1, R2and R3have the meanings described above in connection with the compound of General formulaI. The above reaction can preferably be carried out in the presence of acid, that is Oh how inorganic acid, for example hydrochloric acid, in a suitable polar solvent, such as, for example, 2-methoxyethanol or ethanol, and heated, preferably by boiling under reflux. In some cases, you can get intermediate dihydropyridines, which can be easily converted to a compoundIain the oxidation with a suitable oxidizing agent, such as ammonium nitrate-cerium (IV).

ConnectionIIandIIIare commercially available or can be obtained widely described in the literature methods.

Compounds of the formulaIVyou can obtain when interacting compounds of the formulaVwith the compound of the formulaVI

where G, R1and R2have the above meanings, in the presence of a Lewis acid such as AlCl3in a suitable halogenated solvent such as dichloromethane.

Alternatively, the compounds of formulaIVyou can easily get in the interaction of the compounds of formulaVIIwith the compound of the formulaVIII

where G, R1and R2have the above meanings and R6represents a C1-6-alkyl, in the presence of a base, such as hexamethyldisilazide sodium, in an aprotic polar solvent such as tetrahydrofuran, and at a suitable temperature, preferably at room the Oh temperature.

Alternatively, the compounds of formulaIVyou can easily get in the interaction of the compounds of formulaVIIwith the compound of the formulaIX

in which R1has the above meaning, in the presence of a base, such as diisopropylamide lithium obtained from utility and N,N'-Diisopropylamine, in an aprotic polar solvent such as tetrahydrofuran, and cooled, preferably at -78°C.

Alternatively, the compounds of formulaIVyou can easily get in the interaction of the compounds of formulaVIIwith the compound of the formulaXunder the same conditions described above for the interaction of the compounds of formulaVIIwith the compound of the formulaIX.

Compounds of the formulaVIare commercially available or can be easily obtained from the corresponding carboxylic acid using conventional methods.

ConnectionV,VII,VIIIandIXare commercially available or can be obtained by using widely described in the literature methods.

Compounds of the formulaXyou can easily get in the interaction of the compounds of formulaXI

in which R1has the above meaning and Y represents a halogen, preferably Cl, hydrochlorideN,Aboutdime is ilyjocelyne in the presence of a base, such as triethylamine, in a suitable halogenated solvent, such as, for example, dichloromethane, and cooled, preferably at 0°C.

Alternatively, the compounds of formulaXyou can easily get in the interaction of the compounds of formulaXII

in which R1has the above value, hydrochlorideN,About-dimethylhydroxylamine in the presence of a suitable condensing means, such as, for example,N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide or dicyclohexylcarbodiimide, optionally in the presence of 1-hydroxybenzotriazole, or in the presence of a suitable base, such as pyridine, in a suitable solvent, such as dimethylformamide.

Compounds of the formulaXIare commercially available or can be obtained using standard reactions, proceeding from the corresponding carboxylic acids of the formulaXII.

Acid formulaXIIare commercially available or can be obtained by using widely described in the literature, methods, and they can easily defend.

Alternatively, the compounds of formulaIain which R3=H (i.e., the compound of the formulaIa'), you can receive when interacting propenone formulaXIIIwith the heterocyclic amine of the formulaIIIas shown in the following diagram:

where G, B, D, E, R1and R2have the values described previously. The reaction can be performed in a suitable polar solvent, at an appropriate temperature in the range from room temperature to the boiling point of the solvent and in the presence of acid. Depending on the nature of the substitution may require additionalin situ(place) the acidification stage; this stage can be performed in the same solvent at room temperature, using a suitable oxidant. It is preferable to carry out the reaction ofXIIIwithIIIusing as solvent ethanol at room temperature, in the presence of hydrochloric acid, and optionally ain situapplying nitrate of ammonium cerium (IV) as an oxidant.

Compounds of the formulaXIIIcan be obtained from compounds of the formulaIVas shown in the following diagram:

Alternatively, the compounds of formulaIa'you can get in two stages of the compounds of formulaIVby the condensation reaction with the appropriate aldehydeXIVwith the formation of intermediate compoundsXVand subsequent removal of the protection of the amino group and the closure of the cycle, as shown in the following diagram:

where G, B, D, E, R1and R2have described above meant the I and P represents aminosidine group, such as tert-butoxycarbonyl group. This reaction is preferably carried out in the presence of acid in a suitable polar solvent, such as ethanol, when heated, preferably by boiling under reflux.

Compounds of the formulaXIVyou can get different widely described in the literature methods. For example, they can be obtained from compounds of the formulaIIIby protecting the amino group of a suitable aminosidine group P, for example, by treating Boc2About for the formation of intermediate compoundsXVIand the subsequent election litrownik followed by treatment with dimethylformamide as shown in the following diagram:

Alternatively, some compounds of the formulaIa'where B=N and D=CR4can be obtained from compounds of the formulaXVIIusing the condensation reaction in suitable conditions, as shown in the following diagram:

where G, E, R1, R2and R4have the above values.

Compounds of the formulaXVIIcan be obtained by acylation of amine of the formulaXVIIIunder standard conditions. Amines of the formulaXVIII,in turn, can be obtained from the acids of the formulaXIXthrough rearrangement of kurzius under standard conditions, as shown in the following diagram:

<>

in which G, R1, R2and R4have the above values.

Acid formulaXIXcan be obtained by simultaneous chlorination gloriouse means, such as POCl3or PCl3and hydrolysis of the nitrile groups of the intermediate compoundXXwithout solvent or in a suitable solvent, such as dimethylformamide, and heated, preferably by boiling under reflux, followed by treatment with water.

In General, compounds of formulaXXget in the interaction of the compounds of formulaXXI2-cyanoacetamide, as shown in the following diagram:

in which G, R1and R2have the values described previously. The above reaction is carried out in the presence of a base, such as sodium methylate, in a suitable solvent, such as dimethylformamide, and heated, preferably by boiling under reflux.

Compounds of the formulaXXIyou can easily get in the interaction of the compounds of formulaIVN-(dimethoxymethyl)-N,N-dimethylamine in a suitable solvent, such as tetrahydrofuran.

In General, compounds of formulaIin which A represents N and R3is a group, the identity of the ing the phenyl, replaced R1and in the next position with the N atom to 6-membered Central ring of the bicyclic fragment (i.e. the connectionIbyou can obtain when interacting compounds of the formulaXXIIwith the heterocyclic amine of the formulaXXIIIas shown in the following diagram:

in which G, R1, R2, B, D, and E have the values described previously. The above reaction can preferably be carried out in the presence of an inorganic acid, such as hydrochloric acid, in a suitable polar solvent, such as, for example, 2-methoxyethanol or ethanol, and heated, preferably by boiling under reflux.

Amines of the formulaXXIIIare commercially available or can be obtained by using widely described in the literature, methods, and they can easily defend.

Simple enol ethers of the formulaXXIIyou can obtain when interacting ketone of the formulaIVwith the compound of the formulaXIin which Y represents a halogen, preferably Cl, in the presence of a base, such as NaH, in a suitable polar solvent, such as, for example, dimethylformamide.

In addition, some compounds of the present invention can also be obtained from other compounds of the formulaIusing suitable the reactions of transformation of functional groups in one or several stages, applying well known in organic chemistry reactions in standard experimental conditions.

Thus, for example, the group R4you can convert to a different group, R4, giving rise to new compounds of the formulaI. For example, R4=H can be converted to R4=Br by reacting with a suitable brainwashin means, such as Br2, in a suitable solvent, such as chloroform, at a suitable temperature in the range from room temperature to the boiling point of the solvent;

or R4=H can be converted to R4=Cl by reacting with a suitable gloriouse means, such as N-chlorosuccinimide, in a suitable solvent, such as dimethylformamide, and at a suitable temperature in the range from room temperature to the boiling point of the solvent;

or R4=NH2can be converted to R4=halogen through the formation of diazonium salts with NaNO2subsequent interaction with the copper halide, such as CuBr or CuCl in the presence of acids, such as HBr or HCl;

or R4=NH2can be converted to R4=H through the formation of diazonium salts with NaNO2subsequent interaction with H3PO2in a suitable solvent such as water;

or R4= ester can be converted to R 4= dialkylhydroxylamines or alkanol by interacting with a Grignard reagent, such as methylaniline, in a suitable solvent, such as tetrahydrofuran;

or R4= halogen can be converted to R4=CN by interacting with a cyanide salt, such as CuCN in a suitable solvent, such asN-organic, when heated, preferably by boiling under reflux.

Other transformations on the basis of R4that can also be applied to R2, R3and/or R5to obtain other compounds of the formulaIinclude , for example,

the transformation of CN in CONH2by hydrolysis with a base such as KOH in a suitable solvent, such as tert-butanol, and heated, preferably by boiling under reflux;

the transformation of CN in CH2NH2by reacting with a reducing agent, such as LiAlH4, in a suitable solvent, such as simple diethyl ether;

the transformation of the carboxylic acid ester or amide by reacting respectively with alcohol or an amine, in the presence of an activating means, such asN,N'-dicyclohexylcarbodiimide and 1-hydroxybenzotriazole, and in a suitable solvent, such as dimethylformamide; or, alternatively, the conversion of carboxylic acids in acylchlorides in the conventional conditions of organic synthesis and the subsequent conversion of the latter into ester or amide by reacting respectively with alcohol or amine in the presence of a base, such as triethylamine, in a suitable solvent, such as, for example, dichloromethane or ethanol, and cooled, preferably at 0°C;

the conversion of ester groups to carboxylic acid by hydrolysis in the presence of a base, such as KOH, in a suitable solvent, such as ethanol;

decarboxylation of carboxylic acids by heating at high temperature and preferably without any solvent;

the transformation of the carboxyl group of the carboxylic acid to the amino group by reacting with diphenylphosphorylacetate in the presence of a base, such as, for example, triethylamine, in a suitable solvent, such as dimethylformamide, and at a suitable temperature, preferably at room temperature, followed by treatment with water at a suitable temperature, preferably at 100°C;

the transformation of OH, SH or NH2in the OR, SR, and other or NRR respectively by reacting with an alkylating agent R-X in which R is an Ra, Rb, Rd, Re, Rgor Rh; Ra, Rb, Rd, Re, Rgand Rhhave the meanings described for the General formulaIand X represents a halogen, preferably chlorine or bromine, in the presence of a base, such as triethylamine, sodium hydroxide, sodium carbonate, potassium carbonate or gitignore, among others, in a suitable solvent, such as dichloromethane, chloroform, dimethylformamide or toluene, and at a temperature in the range from room temperature to the boiling point of the solvent;

alternatively, the other can be converted into NCH3R, in which R is an Ra, Rb, Rd, Re, Rgor Rh; and Ra, Rb, Rd, Re, Rgand Rhhave the meanings described for the General formulaIby interaction with formaldehyde in an acidic environment, such as formic acid and preferably by heating;

the conversion of amine to an amide group by reacting with a carboxylic acid in the presence of a suitable condensing means, such as, for example, N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide or dicyclohexylcarbodiimide, optionally in the presence of 1-hydroxybenzotriazole, or in the presence of a suitable base, such as pyridine, in a suitable solvent, such as dimethylformamide; or alternatively the amine can be converted to an amide group by reacting with acylchlorides in the presence of a base, such as triethylamine, in a suitable solvent, such as, for example, dichloromethane, and cooled, preferably at 0°C;

the conversion of an amine into a urea or carbamate using two consecutive stud is th, which include the interaction of the amine with an activating agent, such as triphosgene, in the presence of a base, such as diisopropylethylamine, triethylamine or N-methylmorpholine, in a suitable solvent, such as acetonitrile, or in a halogenated hydrocarbon, such as chloroform or dichloromethane, and then the interaction of the obtained compound with a secondary amine in the case of urea and alcohol in the case of carbamate, in a suitable solvent such as the solvent used in the first stage; or alternatively the amine can be converted to urea or carbamate by reacting respectively with isocyanate or chloroformate in a suitable solvent, for example, such as dimethylformamide, and at a suitable temperature, preferably at room temperature;

the transformation of the amine in sulfonamidnuyu group by interacting with sulphonylchloride, such as sulphonylchloride, optionally in the presence of a base, such as dimethylaminopyridine, in a suitable solvent, such as dioxane, chloroform, dichloromethane or pyridine;

the transformation of the hydroxyl group in the ester group by reacting with a carboxylic acid under standard conditions mentioned previously;

turning sulfanilic group in sulfonyloxy or sulfonyloxy group by mutual the steps with 1 or 2 equivalents, respectively, of a suitable oxidizing agent, such as m-chloroperbenzoic acid, in a suitable solvent such as dichloromethane;

alternatively, the transformation sulfanilic group in sulfonyloxy or sulfonyloxy group can be carried out in the presence of NaWO4and H2O2in a mixture of acetic acid and water, and preferably by heating;

the transformation of primary or secondary hydroxyl group in the group that you want, such as alkylsulfonate or arylsulfonate, such as mesilate or toilet, or halogen, such as Cl, Br or I, by interacting with sulphonylchloride, such as methanesulfonate, in the presence of a base such as pyridine or triethylamine, in a suitable solvent such as dichloromethane or chloroform, or with a halogenation agent, such as SOCl2, in a suitable solvent, such as tetrahydrofuran; such a group to delete then you can replace by interaction with alcohol, amine or thiol, optionally in the presence of a base, such as K2CO3and in a suitable solvent, such as dimethylformamide, 1,2 - dimethoxyethane or acetonitrile;

the conversion of a primary amide to the secondary amide by reacting with an alkylating agent in the presence of a strong base such as sodium hydride, in a suitable solvent and at a temperature, between which Amasa in the range from room temperature to the boiling point of the solvent;

the transformation of the CHO group into the amino group by reacting with an amine in the presence of a reducing agent, such as triacetoxyborohydride sodium in a suitable solvent such as 1,2-dichloroethane or dichloromethane;

turning acetamino group in the aldehyde group by reacting in an acidic environment, such as HCl, at a suitable temperature, preferably at the boiling temperature under reflux;

the transformation of the ester group to an alcohol group by reacting with a reducing agent, such as LiAlH4, in a suitable solvent, such as tetrahydrofuran;

turning sulfonyloxy group associated with the aromatic ring by replacing an amine to obtain the corresponding amino derivatives or alcohol to obtain the corresponding alkoxyimino, or in a suitable solvent or without any solvent and by heating, preferably at a temperature in the range from room temperature to 100°C;

the transformation of the halogen in the other group, in which R is an Ra, Rb, Rd, Re, Rgor Rhand in which Ra, Rb, Rd, Re, Rgand Rhhave the meanings described for the General formulaIby interaction with the amine of the formula H2NR and preferably while heating the AI;

alternatively, the halogen group can be converted to the other group by reacting with an amine of the formula H2NR, in which R is an Ra, Rb, Rd, Re, Rgor Rhand in which Ra, Rb, Rd, Re, Rgand Rhhave the meanings described for the General formulaIin the presence of a base, such as Cs2CO3or tert-butyl sodium, in the presence of a palladium catalyst such as palladium (II)acetate, and a phosphine, such as 2,2'-bis(diphenylphosphino)-1,1'-binaphthyl, in a solvent such as toluene, and preferably by heating; and

the transformation of the halogen group in the phenyl or heteroaryl group by processing phenylboronate or heteroarylboronic acid in the presence of a catalyst, such as palladium catalyst such as palladium (II) acetate or Pd(PPh3)4and the reasons, such as Na2CO3, K2CO3or CsF, in a suitable polar solvent such as 1,2-dimethoxyethane, or in mixtures of toluene with water and preferably with heating.

Similarly, any of the aromatic cycles in the compounds of the present invention can be subjected to reactions of electrophilic aromatic substitution, widely described in the literature.

Some of these reactions cooperation is of morefree explained in more detail in the examples.

As will be obvious to the person skilled in the art, such reactions interconversions can be made based on compounds of the formulaIand on the basis of any intermediate products suitable for synthesis.

As mentioned earlier, the compounds of the present invention act as inhibitors of p38 kinase, including the reduction of proinflammatory cytokines. Therefore, it is expected that the compounds according to the invention is applicable for the treatment or prevention of diseases in which plays the role of p38, in mammals, including humans. Such diseases include diseases caused by overproduction cytokines, such as TNF-α, IL-1, IL-6 or IL-8. These diseases include, but are not limited to, immune, autoimmune and inflammatory diseases, cardiovascular diseases, infectious diseases, disorders associated with bone loss, neurodegenerative diseases, proliferative diseases and the processes associated with the induction of cyclooxygenase-2.

As an example, immune, autoimmune and inflammatory diseases that can be treated or prevented using the compounds of the present invention, include rheumatic diseases (e.g. rheumatoid arthritis, psoriatic arthritis, infectious arthritis, progressive khron the ical arthritis, arthritis deformans, osteoarthritis, traumatic arthritis, gouty arthritis, Reiter syndrome, polyandry, acute synovitis and spondylitis), glomerulonephritis (with nephrotic syndrome with or without nephrotic syndrome), autoimmune hematological disorders (e.g. hemolytic anaemia, aplastic anemia, idiopathic thrombocytopenia, and neutropenia), autoimmune gastritis and autoimmune inflammatory bowel disease (e.g. ulcerative colitis and Crohn's disease), graft rejection, allograft rejection, chronic thyroiditis, graves ' disease, scleroderma, diabetes (type I and type II), active hepatitis (acute and chronic), primary billiary cirrhosis, malignant gravis, multiple sclerosis, systemic erythematous lupus, psoriasis, atopic dermatitis, contact dermatitis, eczema, solar erythema of the skin, chronic renal failure, Stevens-Johnson, idiopathic sprue, sarcoidosis syndrome Gullian-Barre, uveitis, conjunctivitis, keratoconjunctivitis, otitis media, periodontal disease, interstitial pulmonary fibrosis, asthma, bronchitis, rhinitis, sinusitis, pneumoconiosis, syndrome respiratory failure, emphysema, pulmonary fibrosis, silicosis, a chronic inflammatory lung disease (e.g. chronic obstructive C is bolovanje lungs) and other inflammatory or obstructive diseases of the respiratory tract.

Cardiovascular diseases that can be treated or prevented include, among others, myocardial infarction, cardiac hypertrophy, heart failure, ischemic reperfusion disorder, thrombosis, thrombinantithrombin platelet aggregation, acute coronary syndromes, atherosclerosis and cerebral circulation.

Infectious diseases that can be treated or prevented include, among others, sepsis, septic shock, endotoxin shock, sepsis caused by gram-negative bacteria, shigellas, meningitis, cerebral malaria, pneumonia, tuberculosis, viral myocarditis, viral hepatitis (hepatitis A, hepatitis B and hepatitis C), HIV infection, retinitis caused by cytomegalovirus, influenza, herpes, treatment of infections associated with severe burns, myalgia caused by infections, secondary cachexia infections and veterinary viral infections, such as lentivirus, the virus of goats arthritis, viral disease sheep copper-visna, feline immunodeficiency virus, bovine immunodeficiency virus, or canine immunodeficiency virus.

Disorders associated with reseptia bones, which can be treated or prevented include osteoporosis, osteoarthritis, traumatic arthritis and gouty arthritis, and bone disorders associated with multiple myeloma, a fracture of the m bone and bone grafting and in common with all such processes, when it is necessary to induce osteoliticescuu activity and increase bone mass.

Neurodegenerative diseases that can be treated or prevented include, among others, Alzheimer's disease, Parkinson's disease, cerebral ischemia and traumatic neurodegenerative disease.

Proliferative disease that can be treated or prevented include endometriosis, solid tumor, acute and chronic myelogenous leukemia, Kaposi's sarcoma, multiple myeloma, metastatic melanoma, and angiogenic disorders, such as ocular neovascularization and children hemangioma.

Inhibitors of p38 kinase also inhibit the expression of proinflammatory proteins such as cyclooxygenase-2 (COX-2), the enzyme responsible for producing prostaglandins. Therefore, the compounds of the present invention can also be used for the treatment and prevention of diseases mediated COX-2, and, in particular, for the treatment processes, edema, fever, muscle and nerve pain, such as severe headache, pain caused by malignant tumor, dental pain, arthritis pain, hyperalgesia and allodynia.

Tests in vitro and in vivo to determine the compound's ability to inhibit the activity of p38 is well known in this field. For example, the connection being tested is s, you can put in contact with the purified enzyme p38 to determine whether inhibition of p38 activity. Alternatively, to measure the ability of compounds to inhibit the production of cytokines, such as TNFα, for example, in stimulated mononuclear peripheral blood cells (PBMC) or other types of cells, it is possible to apply the test using cells. Detailed description of the tests that can be used to test the biological activity of compounds according to the invention as inhibitors of p38, can be found below (see example 57).

To select the active compounds tested at a concentration of 10 μm in the test described in example 57, should lead to activity that constitutes more than 50% inhibition. More preferably, the compounds must be greater than 50% inhibition at a concentration of 1 μm, and more preferably they have to show more than 50% inhibition at a concentration of 0.1 ám.

The present invention also relates to a pharmaceutical composition which contains a compound of the present invention or its pharmaceutically acceptable salt or MES) and one or more pharmaceutically acceptable excipients. Fillers must be "acceptable" in the sense of compatibility with other ingredients of the composition and not to be harmful for p is the consumer.

Compounds of the present invention can be introduced in the form of any pharmaceutical product, the nature of which, as is well known, will depend on the nature of the active compounds and method of its introduction. You can use any method of administration, for example oral, parenteral, nasal, ocular, rectal and local administration.

Solid compositions for oral administration include tablets, granules and capsules. In any case, the production method is based on a homogeneous mixture, dry granulation or wet granulation of the active compounds with extenders. Such fillers can represent, for example, diluents such as lactose, microcrystalline cellulose, mannitol or calcium phosphate; binders, such as starch, gelatin or povidone; disintegrant, such as sodium carboximetilkrahmal or cross-carmellose sodium; and lubricants, such as magnesium stearate, stearic acid or talc. Using known methods, can be coated tablets with suitable fillers to slow their destruction and absorption in the gastrointestinal tract and thereby provide a prolonged action over a long period, or simply to improve their organoleptic properties or stability. The active compound can also enter the ü in part by drawing on the inert pills, using natural or synthetic film coating. You can also use soft gelatin capsules in which the active compound is mixed with water or an oil medium, for example coconut oil, mineral oil or olive oil.

Powders and granules for the preparation of suspensions for oral administration by the addition of water can be obtained by mixing the active compounds with dispersing or wetting means; suspendresume means and preservatives. You can also add other fillers, such as sweeteners, perfumes and dyes.

Liquid forms for oral administration include emulsions, solutions, suspensions, syrups and elixirs containing commonly used inert diluent such as purified water, ethanol, sorbitol, glycerol, glycols (macrogol) and propylene glycol. Such compositions may also contain auxiliary agents such as wetting, suspendresume tools, sweeteners, fragrances, preservatives and buffers.

Preparations for injection according to the present invention for parenteral administration include sterile solutions, suspensions or emulsions in aqueous or nonaqueous solvent, such as propylene glycol, polyethylene glycol or vegetable oil. Such compositions can also contain auxiliary means, which as a wetting means, emulsifiers, dispersants and preservatives. They can also be sterilized by any known method, or be prepared in the form of sterile solid compositions, which will dissolve in water or any other sterile environment for injection immediately before use. You can also proceed from sterile materials and maintain them in a sterile environment throughout the production process.

For rectal injection of the active compound can preferably be obtained in the form of a suppository-based oils, such as vegetable oils, solid or semi-synthetic glycerides, or on the basis of hydrophilic substances, such as polyethylene glycol (macrogol).

Compounds of the present invention can also be obtained in the form of a preparation for topical application for the treatment of pathologies occurring in zones or organs available for such an introduction, such as eyes, skin and intestines. Preparations include creams, lotions, gels, powders, solutions, and patches where the connection is distributed or dissolved in suitable fillers.

For nasal injection or inhalation, the compound can be obtained in the form of an aerosol and can be a convenient way to release, using suitable propellants.

Dosage and frequency of doses, among other factors, will depend on prirody the severity of the disease, to be treated, the age, General condition and body weight of the patient, and the specific input connection and a way of introduction. In the above example, a suitable dosage range is from about 0.01 mg/kg to about 100 mg/kg / day, the dosage can be entered once or in divided doses.

The invention is illustrated by the following examples.

Examples

Used the following abbreviations:

ACN: acetonitrile

BuLi: n-utility

DMF: dimethylformamide

DMSO: dimethyl sulfoxide

EtOAc: ethyl acetate

EtOH: ethanol

KOtBu: tert-butyl potassium

LC-MS: liquid chromatography-mass spectrometry

MeOH: methanol

NaOMe: sodium methylate

NH4OAc: ammonium acetate

NMM: N-methylmorpholine

NMP: N-organic

TEA: triethylamine

TFA: triperoxonane acid

THF: tetrahydrofuran

TR: retention time

To obtain the spectrum of the LC-MS was applied the following chromatographic methods.

Method 1:column Tracer Excel 120, ODSB 5 μm (10 mm × 0.21 mm), column temperature: 30°C, flow: 0.35 ml/min, eluent: A=ACN, B=0.1% of HCOOH, gradient: 0 min 10% A - 10 min 90% A.

Method 2:column X-Terra MS C18 5 μm, 150 mm × 2.1 mm), column temperature: 30°C, flow: 0.35 ml/min, eluent: A=ACN, B=10 mm NH4OAc (pH=6,80), gradient: 0 min 10% A - 10 min 90% A.

Method 3:column 3.5 µm X-Terra MS C18 2×4.6 mm; flow: 1 ml/min; detection: 210 nm; column temperature: 40°C; solvent A: 0.05% of TFA in ACN/H2About=9/1 (about./vol.); solvent B: 0.05% of TFA in H2O; gradient: solvent A/B=0/100-100/0 (about./about.) within 5 minutes

To determine the retention time was used the following methods analytical HPLC.

Method 4:column (5 μm Luna C-18(2) 150×4.6 mm; flow: 1 ml/min; detection: 210 nm; column temperature: 40°C; solvent A: ACN/H2About=1/9 (about./vol.); solvent B: ACN; solvent C: 0.1 M aqueous solution of TFA; gradient: solvent A/B/C=77/20/3-15/82/3 (about./about./about.) within 30 min, and then continuously for an additional 10 min at A/B/C=15/82/3 (about./about./vol.).

Method 5:column (5 μm Luna C-18(2) 150×4.6 mm; flow: 1 ml/min; detection: 210 nm; column temperature: 40°C; solvent A is 0.1% TFA in ACN/H2About=1/9 (about./vol.); solvent B is 0.1% TFA in ACN; gradient: solvent A/B=100/0-0/100 (about./about.) within 30 minutes

Method 6:Column (5 μm Atlantis dC 18 150×4.6 mm; flow: 1 ml/min; detection: 210 nm; column temperature: 40°C; solvent A is 0.1% TFA in ACN/H2About=1/9 (about./vol.); solvent B is 0.1% TFA in ACN; gradient: solvent A/B=100/0-0/100 (about./about.) within 30 minutes

Preparative HPLC was performed under the following chromatographic conditions:

column Luna 10 m C18(2) [250×50 mm); eluent: 0.1% TFA solution in mixtures of ACN/water in order of decreasing polarity.

The reaction, carried out under the action of micro is analogo radiation, held in the synthesizer Biotage Initiator Microwave Synthesizer. The reaction mixture was placed in a sealed tube and heated at a constant temperature (which is specified in each example) under the action of microwave irradiation in the range from 0 to 75 watts. Then the reaction mixture was cooled to room temperature.

REFERENCE EXAMPLE 1

1-(4-Forfinal)-2-(4-pyridyl)alanon

a) Ethyl 4-perbenzoate

To a solution of TEA (28.4 ml, 211 mmol) in EtOH (143 ml) and cooled to 0°C and in an atmosphere of argon was slowly added 4-perbenzoate (33,50 g, 25 ml) and the resulting mixture was stirred at room temperature for 7 hours. The obtained product was concentrated and to the residue was added EtOAc and water. The phases were separated and the aqueous phase re-extracted with EtOAc. The combined organic extracts were washed with 10% aqueous solution of NaHCO3, dried over Na2SO4and concentrated to dryness, thus obtaining 35,00 g of the desired compound (yield 98%).

1H NMR (300 MHz, CDCl3) δ (TMS): of 1.39 (t, J=7.2 Hz, 3H), 4,36 (s, J=7.2 Hz, 2H), 7,12 (m, 2H), with 8.05 (m, 2H).

(b) Specified in the header connection

To a mixture of 4-methylpyridine (33,60 g, 356,0 mmol) and ethyl 4-perbenzoate (60,53 g, 356,0 mmol, obtained in paragraph (a) in THF (350 ml), cooled to 10°C in argon atmosphere was added 2 N hexamethyldisilazide sodium (281 ml) so that the temperature did not exceed 10°C. Immediately after the end the of the addition the mixture was stirred at room temperature for 18 hours. The mixture was cooled to 5-10°C and was added water (200 ml). The aqueous phase was separated and was twice extracted with EtOAc (200 and 100 ml, respectively). The combined organic extracts were washed with water and concentrated. The crude product was purified by recrystallization from EtOAc (40 ml) and cyclohexane (200 ml), while receiving 38,79 g specified in the connection header. The mother liquor was purified column chromatography, thus obtaining 10,24 g specified in the title compound (total yield: 64%).

1H NMR (300 MHz, CDCl3) δ (TMS): the 4.29 (s, 2H), 7,14-7.23 percent (complex signal, 4H), with 8.05 (m, 2H), 8,59 (DD, Jo=1,6 Hz, Jm=4.4 Hz, 2H).

REFERENCE EXAMPLE 2

1-Phenyl-2-(4-pyridyl)alanon

The solution Diisopropylamine (22 ml, 15,03 mmol) in THF (200 ml) was cooled in an argon atmosphere to -78°C. Then was added dropwise BuLi (96 ml of 1.6 M solution in hexane, 153,0 mmol). An hour later was added a solution of 4-methylpyridine (15,00 g, owed 161.1 mmol) in THF (75 ml) and allowed to warm the mixture to 0°C. the Mixture was stirred at the same temperature for 30 minutes Then the mixture was cooled to -78°C, was added benzonitrile (18,27 g, 177,2 mmol) in THF (75 ml) and the resulting mixture was stirred at -78°C for 2 hours. The mixture was stirred at room temperature overnight. Was added water (225 ml), the mixture was cooled in a water bath with ice and brought the pH to 1 with 48% HBr. The organic phase is separated. The aqueous phase was heated at the boil under reflux for 2 hours, allowed to cool and was extracted with simple diethyl ether. the pH of the aqueous phase was brought to neutral pH with 1 N NaOH and was extracted with EtOAc. The organic phase was dried over Na2SO4and concentrated to dryness, thus obtaining 28,53 g specified in the title compound (yield 90%).

1H NMR (300 MHz, CDCl3) δ (TMS): the 4.29 (s, 2H), 7,20 (DD, Jo=1,6 Hz, Jm=4.4 Hz, 2H), 7,49 (m, 2H), 7,58 (m, 1H), 8,00 (d, J=8,2 Hz, 2H), 8,56 (DD, Jo=1,6 Hz, Jm=4.4 Hz, 2H).

REFERENCE EXAMPLE 3

1-(4-Forfinal)-2-(4-pyridyl)vinyl 4-perbenzoate

To a suspension of NaH (0,81 g of 18.6 mmol) in DMF (30 ml) in an argon atmosphere and cooled to 0°C was added a solution of 1-(4-forfinal)-2-(4-pyridyl)ethanone (2.00 g, 9.3 mmol, obtained in reference example 1) in DMF (15 ml) and the resulting mixture was stirred at room temperature for 30 minutes Then the mixture was cooled to 0°C was added a solution of 4-tormentilla (2,95 g, 1.9 mmol) in DMF (10 ml). The mixture was stirred at room temperature overnight. Added water and the solvent evaporated. The residue was dissolved in a mixture of CHCl3-water and separated phases. The aqueous phase was extracted with CHCl3(×3). The organic phase is twice washed with water, dried over Na2SO4and concentrated to dryness. The crude product was purified chromium is cografya on silica gel, using as eluent a mixture of hexane/EtOAc in order of increasing polarity, and while receiving and 0.98 g of the desired compound as a yellow solid (yield 31%).

1H NMR (300 MHz, CDCl3) δ (TMS): of 6.68 (s, 1H), 7,11 (t, J=8.6 Hz, 2H), 7,29 (t, J=8.6 Hz, 2H), 7,39 (d, J=6.0 Hz, 2H), 7,60 (DD, Jo=5,2 Hz, Jm=8,8 Hz, 2H), 8,27 (DD, Jo=5.4 Hz, Jm=8,8 Hz, 2H), 8,58 (d, J=6.0 Hz, 2H).

REFERENCE EXAMPLE 4

1-Phenyl-2-(4-pyridyl)vinylbenzoate

Specified in the title compound (yield 62%) was obtained by following the procedure similar to that described in reference example 3, but using 1-phenyl-2-(4-pyridyl)alanon (obtained in reference example 2) instead of 1-(4-forfinal)-2-(4-pyridyl)ethanone and benzoyl chloride instead of 4-tormentilla, getting mentioned in the title compound (yield 62%).

LC-MS (method 1): tR=7,05 min; m/z=302,1 [M+H]+.

REFERENCE EXAMPLE 5

1-(4-Forfinal)-2-(2-methylsulfonylamino-4-yl)propenone

a) 4-Methyl-2-(methylsulfanyl)pyrimidine

To a solution of NaOH (7,46 g, 186,4 mmol) in water (120 ml) was added 4-methylpyrimidin-2-toledoblade (13,78 g, 84,7 mmol) and then in argon atmosphere was added dropwise logmean (13,23 g, 93,2 mmol). The mixture was stirred at room temperature for 2 hours and then was extracted with CH2Cl2(2×). The organic phase was dried over Na2SO4and concentrated to dryness. P the obtained crude product was purified by chromatography on silica gel, using as eluent a mixture of hexane/EtOAc in order of increasing polarity, and while receiving 10,26 g of the desired compound (yield: 86%).

b) 1-(4-Forfinal)-2-(2-methylsulfonylamino-4-yl)alanon

To a solution of 4-methyl-2-(methylsulfanyl)pyrimidine (21,00 g, 150,0 mmol) and ethyl 4-perbenzoate (25,14 g, 150,0 mmol) in THF (300 ml) in an argon atmosphere was added dropwise a solution of hexamethyldisilazide sodium (150 ml, 2 M solution in THF, 300 mmol) in THF (150 ml) under cooling in a bath with ice. The mixture was stirred at room temperature for 2 hours. Was added a saturated solution of NH4Cl and the solvent evaporated. The residue was placed in a mixture of EtOAc and water and separated phases. The aqueous phase was extracted with EtOAc. The combined organic phases were washed with saturated salt solution, dried over Na2SO4and concentrated to dryness, thus obtaining 36,36 g specified in the title compound (yield: 93%).

c) 1-(4-Forfinal)-2-(2-methylsulfonylamino-4-yl)propenone

To a solution of N,N,N',N'-tetramethylmethylenediamine (0,421 ml of 3.05 mmol) in anhydrous CH2Cl2(2.5 ml) at -15°C was added dropwise a solution of 1-(4-forfinal)-2-(2-methylsulfonylamino-4-yl)ethanone (0.5 g, at 1.91 mmol) and acetic anhydride (0,397 ml, 4.20 mmol) in anhydrous CH2Cl2(5 ml). The reaction mixture was stirred at the same temperature under nitrogen atmosphere for 10 minutes. PEFC is what was added a mixture of diethyl ether/water (1:1). The organic phase is washed with water (2×) and saturated salt solution (2×), dried over MgSO4and concentrated to dryness, thus obtaining 483 mg specified in the header of the product as a colourless oil (yield: 92%).

MS: m/z=275 [M+H]+.

REFERENCE EXAMPLE 6

1-(4-Methoxyphenyl)-2-(2-methylsulfonylamino-4-yl)propenone

a) 1-(4-Methoxyphenyl)-2-(2-methylsulfonylamino-4-yl)alanon

Specified in the title compound (7.2 g, yield 87%) was obtained by following the procedure similar to that described in reference example 5b, but using ethyl 4-methoxybenzoate instead of ethyl 4-perbenzoate.

HPLC (method 6): tR=20,45 min; MS: mz=275 [M+H]+.

b) 1-(4-Methoxyphenyl)-2-(2-methylsulfonylamino-4-yl)propenone

Specified in the title compound (320 mg, yield: 80%) was obtained by following the procedure similar to that described in reference example 5c, but using 1-(4-methoxyphenyl)-2-(2-methylsulfonylamino-4-yl)Etalon instead of 1-(4-forfinal)-2-(2-methylsulfonylamino-4-yl)ethanone.

HPLC (method 6): tR=21,14 min; MS: m/z=287 [M+H]+.

REFERENCE EXAMPLE 7

Methyl ester of 4-amino-1H-pyrazole-3-carboxylic acid

To a solution of complex methyl ester 4-nitro-1H-pyrazole-3-carboxylic acid (1.3 g, 7.6 mmol) in MeOH (100 ml) was added ammonium formate (3,35 g, 53.2 mmol) and 5% palladium-on-coal 225 mg). The reaction mixture was stirred for 17 hours at room temperature in a nitrogen atmosphere. When removing the catalyst by filtration followed by evaporation of the solvent was obtained the crude product, representing specified in the title compound, as a brown solid (yield: 95%).

REFERENCE EXAMPLE 8

Complex tert-butyl ester (4-formyl-5-methylisoxazol-3-yl)carbamino acid

a) Complex tert-butyl ester (5-methylisoxazol-3-yl)carbamino acid

To a solution of 3-amino-5-methylisoxazole (5 g, 51 mmol) in pyridine (80 ml) at room temperature was added di-tert-BUTYLCARBAMATE (11.1 g, 51 mmol). The reaction mixture was stirred over night. Was added an aqueous solution of NaOH in MeOH and stirred for 3 hours at room temperature. Added EtOAc and water and separated phases. The aqueous phase was extracted with EtOAc. The combined organic phases were dried over Na2SO4and concentrated to dryness. The crude product was purified by chromatography on silica gel, using as eluent a mixture of heptane/EtOAc in order of increasing polarity, and while receiving 6,44 g specified in the title compound (yield: 63%)

b) a compound tert-butyl ester (4-formyl-5-methylisoxazol-3-yl)carbamino acid

To a solution of complex tert-butyl ester (5-m is telesocial-3-yl)carbamino acid (2 g, 10.1 mmol, obtained in reference example 8a) in THF (50 ml) was added BuLi (of 1.6 M solution in hexane, to 14.5 ml, 23.2 mmol) at -78°C and in an atmosphere of N2. The reaction mixture was stirred for 30 minutes at -78°C and then for 30 minutes at room temperature. After cooling to -78°C was added DMF (2 ml, and 24.2 mmol) and stirred the reaction mixture for 2 hours at room temperature. Added EtOAc and water and separated phases. The aqueous phase was extracted with EtOAc. The combined organic phases are washed with water, dried over Na2SO4and concentrated to dryness. The crude product was purified by chromatography on silica gel, using as eluent a mixture of heptane/EtOAc in order of increasing polarity, and while receiving 498 mg of the desired compound (yield: 22%).

REFERENCE EXAMPLE 9

2-Pyridin-4-yl-1-(3-formationl)alanon

a)N-methoxy-N-methyl-3-(trifluoromethyl)benzamid

In the volumetric flask in a nitrogen atmosphere at 0°C was injected hydrochloride of N,O-dimethylhydroxylamine (a 7.62 g, 70 mmol) and CH2Cl2(135 ml). Was added 3-(trifluoromethyl)benzoyl chloride (14,81 g, 71 mmol) followed by slow addition of TEA (15,81 g, 156,2 mmol). The reaction mixture was stirred for 30 minutes at 5°C and allowed to reach room temperature. The reaction mixture is washed with 5%aqueous citric acid (60 ml) and 5%aqueous the solution of NaHCO 3(60 ml). The aqueous phase was extracted with CH2Cl2. The organic phase was dried over Na2SO4and concentrated to dryness, thus obtaining a 16.8 g of the desired compound (yield: 100%).

b) 2-Pyridin-4-yl-1-(3-triptoreline)alanon

To a solution of Diisopropylamine (15.3 ml, 108 mmol) in THF (170 ml) and cooled to -78°C was added dropwise and under nitrogen atmosphere BuLi (68 ml of 1.6 M solution in hexane, 108 mmol). After 5 minutes the reaction mixture was allowed to reach -30°C and then stirred at the same temperature for 30 minutes. At the same temperature for 20 minutes was added a solution of 4-methylpyridine (7,07 ml, for 72.1 mmol) in THF (57 ml). The mixture was stirred at 0°C for 15 minutes and within 30 minutes the solution was added toN-methoxy-N-methyl-3-(trifluoromethyl)benzamide (obtained in paragraph (a) in THF (57 ml). The reaction mixture was allowed to reach room temperature. Was added water (100 ml) and EtOAc (100 ml) and the mixture was stirred for 30 minutes. The organic phase was separated, dried over Na2SO4and concentrated to dryness, thus obtaining 16.2 g of the desired compound (yield: 76%).

REFERENCE EXAMPLE 10

N-[2-chloro-6-(4-forfinal)-5-(2-methylsulfonylamino-4-yl)pyridine-3-yl]ndimethylacetamide

a) 3-(Dimethylamino)-1-(4-forfinal)-2-[2-(methylsulfanyl)pyrimidine-4-yl]prop-2-EN-1-he

To a solution of 1-(4-FPO is phenyl)-2-(2-methylsulfonylamino-4-yl)ethanone (37,8 g, 144 mmol, obtained in reference example 5b) in anhydrous THF (500 ml) under nitrogen atmosphere was added dimethylformamidine (27.7 g, 328 mmol). The reaction mixture was stirred over night at room temperature. The solvent evaporated, thus obtaining 49,14 g specified in the title compound (yield: quantitative).

b) 6-(4-Forfinal)-2-(hydroxy)-5-(2-methylsulfonylamino-4-yl)pyridine-3-carbonitrile

To a solution of 3-(dimethylamino)-1-(4-forfinal)-2-[2-(methylsulfanyl)pyrimidine-4-yl]prop-2-EN-1-it (4.68 g, 14.7 mmol, obtained in reference example 10a) in DMF (60 ml) under nitrogen atmosphere was added 2-cyanoacetamide (1.42 g, 16.9% mmol). Then was added NaOMe (1.75 g, 32,4 mmol) and heated the mixture at boiling under reflux for 1 hour. The mixture was allowed to cool, concentrated and diluted with water. Brought the pH to 4 using 1 N HCl. The crude product was purified by chromatography on silica gel, using as eluent a mixture of heptane/EtOAc in order of increasing polarity, and while receiving 2,95 g of the desired compound (yield: 59%).

C) 2-Chloro-6-(4-forfinal)-5-(2-methylsulfonylamino-4-yl)nicotinic acid

To a solution of 6-(4-forfinal)-2-(hydroxy)-5-(2-methylsulfonylamino-4-yl)pyridine-3-carbonitrile (1.10 g, 3.25 mmol, obtained in reference example 10b) in DMF (2.5 ml) under nitrogen atmosphere at room temperature was added caloric phosphorus (4 ml). The mixture was heated at boiling under reflux and was stirred for 4 hours. Then the mixture was cooled to room temperature, poured into ice water and was extracted with EtOAc (2×). The combined organic phases were washed with 0.2 M NaOH solution and the layers were separated. The aqueous phase was acidified using 2 M HCl solution and then was extracted with EtOAc (2×). The combined organic phases were washed with saturated salt solution (1×), dried over Na2SO4and concentrated to dryness, thus obtaining 0,91 g specified in the title compound (yield: 75%).

MS: m/z=376 [M+H]+.

d) 2-Chloro-6-(4-forfinal)-5-(2-methylsulfonylamino-4-yl)pyridine-3-ylamine

To a solution of 2-chloro-6-(4-forfinal)-5-(2-methylsulfonylamino-4-yl)nicotinic acid (0,91 g, 2,42 mmol, obtained in reference example 10c) in NMP (12 ml) was sequentially added at room temperature and under nitrogen atmosphere TEA (0,43 ml of 3.15 mmol) and diphenylphosphoryl (0,57 ml of 2.66 mmol). The mixture was heated to 90°C and was stirred for 2 hours. Then the mixture was cooled to room temperature, the solution was added NaHCO3and was extracted with EtOAc (2×). The combined organic phases were washed with a solution of NaHCO3(1×) and saturated salt solution (1×), dried over Na2SO4and concentrated to dryness, thus obtaining 0.75 g specified in the title compound (yield: 89%).

MS: m/z=347 [M+H]+.

e)N-[2-chloro-6-(4-forfinal)-5-(2-methylsulfonylamino-4-yl)pyridine-3-yl]ndimethylacetamide

To a solution of 2-chloro-6-(4-forfinal)-5-(2-methylsulfonylamino-4-yl)pyridine-3-ylamine (to 0.19 g, 0.55 mmol, obtained in reference example 10d) in dichloromethane (6 ml) successively at 0°C was added pyridine (0,22 ml, is 2.74 mmol) and acetylchloride (0,078 ml, 1.10 mmol). The mixture was stirred for 1 hour. Solution was added NaHCO3and was extracted with dichloromethane (2×). The combined organic phases were washed with a solution of NaHCO3(2×), 2 M HCl solution (2×) and saturated salt solution (1×), dried over Na2SO4and concentrated to dryness, thus obtaining 0.20 g specified in the title compound (yield: 94%).

MS: m/z=389 [M+H]+.

EXAMPLE 1

Methyl 5,7-bis-(4-forfinal)-6-(4-pyridyl)thieno[3,2-b]pyridine-3-carboxylate

To a solution of 1-(4-forfinal)-2-(4-pyridyl)ethanone (0,30 g, 1.4 mmol, obtained in reference example 1) in 2-methoxyethanol (2 ml) in an argon atmosphere was added 4-forbindelse (170 mg, 1.4 mmol), methyl 4-aminothiophene-3-carboxylate (240 mg, 1.5 mmol), 2-methoxyethanol (2 ml) and HCl (37%, 40 mg, 0.4 mmol). The resulting mixture was heated at the boil under reflux overnight. Gave the mixture to cool and added CHCl3, MeOH (1 drop) and 1 N NaOH solution. The aqueous phase was extracted with CHCl3(×3). The combined organic extracts dried the over Na 2SO4and the solvent evaporated. The crude product was purified by chromatography on silica gel, using as eluent a mixture of hexane/EtOAc in order of increasing polarity and thereby obtain 0.52 g of the desired compound (yield 83%).

LC-MS (method 1): tR=8,66 min; m/z=459,1 [M+H]+.

Following a procedure similar to that described in example 1, but using in each case the corresponding starting compound were obtained products are shown in the table:

ExampleConnection nameThe source connectionsLC-MS
MethodtR
(min)
m/z [M+H]+
2Methyl 4,6-bis-(4-forfinal)-5-(4-pyridyl)furo[2,3-b]pyridine-2-carboxylate;Referential example 1, methyl 5-aminopurin-2-carboxylate and 4-forbindelse18,75443,0
3Methyl 5,7-bis-(4-forfinal)-1-methyl-6-(4-pyridyl)pyrrolo[3,2-b]pyridine-2-carboxylate Referential example 1, methyl-4-amino-1-methylpyrrole-2-carboxylate and 4-forbindelse17,83456,1
44,6-Bis-(4-forfinal)-3-methyl-5-(4-pyridyl)isoxazole-[5,4-b]pyridineReference example 1,5-amino-3-(methyl)isoxazol-and 4-forbindelse1at 8.36400,1
5Ethyl 5,7-bis-(4-forfinal)-1-methyl-6-(4-pyridyl)imidazo[4,5-b]pyridine-2-carboxylateReference example 1 ethyl-4-amino-1-Mei-2-carboxylate and 4-forbindelse17,01471,2

EXAMPLE 6

[5,7-Bis-(4-forfinal)-1-methyl-6-(4-pyridyl)pyrrolo[3,2-b]pyridine-2-yl]methanol

Suspension CaCl2(73 mg, 0.7 mmol) and NaBH4(50 mg, 1.3 mmol) in THF (16 ml) was heated at the boil under reflux for 4 hours in argon atmosphere. The resulting mixture was cooled to 30°C and was added dropwise a solution of methyl 5,7-bis-(4-forfinal)-1-methyl-6-(4-pyridyl)pyrrolo[3,2-b]pyridine-2-carboxylate (100 mg, 0.2 mmol, obtained in example 3) in THF (24 ml). The resulting mixture was heated at boiling the situation under reflux for 6 hours. Gave cooled mixture was poured into ice and THF evaporated. The residue was twice extracted with CH2Cl2. The combined organic extracts were dried over Na2SO4and the solvent evaporated. The crude product was purified by chromatography on silica gel, using as eluent a mixture of hexane/tO in order of increasing polarity, and while receiving 25 mg of the desired compound (yield 26%).

LC-MS (method 1): tR=to 4.41 min; m/z=428,1 [M+H]+.

EXAMPLE 7

[5,7-Bis-(4-forfinal)-1-methyl-6-(4-pyridyl)imidazo[4,5-b]pyridine-2-yl]methanol

Specified in the title compound was obtained by following the procedure similar to that described in example 6, but on the basis of ethyl 5,7-bis-(4-forfinal)-1-methyl-6-(4-pyridyl)imidazo[4,5-b]pyridine-2-carboxylate (obtained in example 5).

LC-MS (method 1): tR=5,00 min; m/z=429,1 [M+H]+.

EXAMPLE 8

5,7-Bis-(4-forfinal)-2-methyl-6-(4-pyridyl)pyrazolo[1,5-a]pyrimidine

A solution of 3-amino-5-methyl-2H-pyrazole (70 mg, 0.7 mmol) in EtOH (2 ml) and 37% HCl (1 drop) in an argon atmosphere was added in excess to 1-(4-forfinal)-2-(4-pyridyl)vinyl 4-perbenzoate (0,22 g, 65,0 mmol, obtained in reference example 3). The resulting mixture was heated at the boil under reflux overnight. Gave the mixture to cool and the solvent evaporated. Received the initial crude product was purified by chromatography on silica gel, using as eluent a mixture of hexane/tO in order of increasing polarity, and while receiving 9 mg specified in the title compound (yield 3%).

LC-MS (method 1, the flow of 0.30 ml/min): tR=8,04 min; m/z=399,1 [M+H]+.

EXAMPLE 9

2-Methyl-5,7-diphenyl-6-(4-pyridyl)pyrazolo[1,5-a]pyrimidine

Specified in the title compound was obtained by following the procedure similar to that described in example 8, but using instead of 1-(4-forfinal)-2-(4-pyridyl)vinyl-4-perbenzoate 1-phenyl-2-(4-pyridyl)vinylbenzoate (obtained in reference example 4).

LC-MS (method 1, the flow of 0.30 ml/min): tR=6,72 min; m/z=363,2 [M+H]+.

EXAMPLE 10

5,7-Bis-(4-forfinal)-1-methyl-6-(4-pyridyl)imidazo[4,5-b]pyridine

a) 5,7-Bis-(4-forfinal)-1-methyl-6-(4-pyridyl)imidazo[4,5-b]pyridine-2-carboxylic acid

To a solution of ethyl 5,7-bis-(4-forfinal)-1-methyl-6-(4-pyridyl)imidazo[4,5-b]pyridine-2-carboxylate (0.29 grams, 0.6 mmol, obtained in example 5) in EtOH (13 ml) was added a solution of KOH (0,42 g, 6.3 mmol) in water (2.5 ml) and the resulting mixture was heated at the boil under reflux for 2 hours. Gave the mixture to cool and the solvent evaporated. Added water and then brought the pH of the mixture to pH 6-7 with 1 N HCl. The mixture was extracted with EtOAc, the organic phase was dried over Na2SO4and the solvent evaporated. The crude product is CT was purified by chromatography on silica gel, using as eluent a mixture of EtOAc/MeOH/NH3in order of increasing polarity and getting 253 mg of the desired compound (quantitative yield).

LC-MS (method 1): tR=5,16 min; m/z=399,2 [M-CO2+H]+.

(b) Specified in the header connection

5,7-Bis-(4-forfinal)-1-methyl-6-(4-pyridyl)imidazo[4,5-b]pyridine-2-carboxylic acid (50 mg, 0.1 mmol, obtained in paragraph (a) was heated at 200°C during the night. The crude product was purified by chromatography on silica gel, using as eluent a mixture of EtOAc/MeOH in increasing order of polarity and thereby obtain 39 mg specified in the title compound (yield 89%).

LC-MS (method 1): tR=lower than the 5.37 min; m/z=399,1 [M+H]+.

EXAMPLE 11

5,7-Bis-(4-forfinal)-N-(2-hydroxyethyl)-6-(4-pyridyl)thieno[3,2-b]pyridine-3-carboxamide

a) 5,7-Bis-(4-forfinal)-6-(4-pyridyl)thieno[3,2-b]pyridine-3-carboxylic acid

Specified in the title compound was obtained by following the procedure similar to that described in example 10, but using as starting compound methyl 5,7-bis-(4-forfinal)-6-(4-pyridyl)thieno[3,2-b]pyridine-3-carboxylate (obtained in example 1).

LC-MS (method 1): tR=by 8.22 min; m/z=445,1 [M+H]+.

(b) Specified in the header connection

To a solution of 5,7-bis-(4-forfinal)-6-(4-pyridyl)thieno[3,2-b]pyridine-3-carboxylic acid 100 mg, 0.2 mmol, obtained in paragraph (a) in DMF (1.5 ml) was added 1-hydroxybenzotriazole (31 mg, 0.2 mmol),N-(3-dimethylaminopropyl)-N'ethylcarbodiimide (53 mg, 0.3 mmol) and NMM (35 mg, 0.3 mmol) and the resulting mixture was stirred at room temperature for 1 hour. Was added 2-aminoethanol (14 mg, 0.2 mmol) and stirred the mixture at room temperature over night. The mixture was poured into water and was extracted with CHCl3. The organic phase was dried over Na2SO4and concentrated. The crude product was purified by chromatography on silica gel, using as eluent a mixture of EtOAc/MeOH in increasing order of polarity and thereby obtain 41 mg specified in the title compound (yield 40%).

LC-MS (method 1): tR=6,74 min; m/z=488,1 [M+H]+.

EXAMPLE 12

5,7-Bis-(4-forfinal)-1-methyl-6-(4-pyridyl)pyrrolo[3,2-b]pyridine-2-carboxamide

a) 5,7-Bis-(4-forfinal)-1-methyl-6-(4-pyridyl)pyrrolo[3,2-b]pyridine-2-carboxylic acid

Specified in the title compound was obtained by following the procedure similar to that described in example 10, but using as starting compound methyl 5,7-bis-(4-forfinal)-1-methyl-6-(4-pyridyl)pyrrolo[3,2-b]pyridine-2-carboxylate (obtained in example 3).

LC-MS (method 1): tR=5,32 min; m/z=442,1 [M+H]+.

(b) Specified in the header connection

Specified in the header soy is inania received, following a procedure similar to that described in example 11, but using as starting compounds 5,7-bis-(4-forfinal)-1-methyl-6-(4-pyridyl)pyrrolo[3,2-b]pyridine-2-carboxylic acid (obtained in PA) and ammonia.

LC-MS (method 1): tR=5,12 min; m/z=441,1 [M+H]+.

Following a procedure similar to that described in .b) of example 12, but using in each case the corresponding starting compound were obtained products are shown in the following table:

ExampleConnection nameThe source connectionsLC-MS
MethodtR
(min)
m/z [M+H]+
135,7-Bis-(4-forfinal)-N-(2-hydroxyethyl)-1-methyl-6-(4-pyridyl)pyrrolo[3,2-b]pyridine-2-carboxamidep.a.) of example 12 and 2-aminoethanol14,86485,1
14[5,7-Bis-(4-forfinal)-1-methyl-6-(4-pyridyl)pyrrolo[3,2-b]pyridine-2-yl]morpholine-4-ylmethanolPA) PR is a measure of 12 and morpholine 15,44511,1

EXAMPLE 15

3-Amino-5,7-bis-(4-forfinal)-6-(4-pyridyl)thieno[3,2-b]pyridine

To a solution of 5,7-bis-(4-forfinal)-6-(4-pyridyl)thieno[3,2-b]pyridine-3-carboxylic acid (100 mg, 0.2 mmol, obtained in PA) of example 11) in DMF (0,13 ml) in an argon atmosphere was added a solution of TEA (35 mg, 0.3 mmol) in DMF (0.33 ml) and then was added dropwise a solution of diphenylphosphinite (95 mg, 0.3 mmol) in DMF (0.33 ml). The resulting mixture was stirred at room temperature for 3 hours. Was slowly added water (2 ml) and the mixture was heated at 100°C for 1 hour. Gave the mixture to cool to room temperature and the solvent evaporated. The residue was diluted with CHCl3and washed with saturated solution of NaHCO3(×3). The organic phase was dried over Na2SO4and concentrated. The crude product was purified by chromatography on silica gel, using as eluent a mixture of hexane/tO in order of increasing polarity and thereby obtain 21 mg specified in the title compound (yield 23%).

LC-MS (method 2): tR=9,46 min; m/z=416,1 [M+H]+.

EXAMPLE 16

2-[4,6-Bis-(4-forfinal)-5-(4-pyridyl)furo[2,3-b]pyridine-2-yl]propane-2-ol

To a solution of methyl 4,6-bis-(4-forfinal)-5-(4-pyridyl)furo[2,3-b]pyridine-2-carboxylate (200 mg, 0.4 mmol, polucen the th in example 2) in THF (0.7 ml), cooled to 0°C in an argon atmosphere was added a 3 M solution of methylmagnesium in THF (of 0.60 ml, 1.8 mmol). The resulting mixture was stirred at room temperature for 2 hours. Added EtOAc and a saturated solution of NH4Cl and separated phases. The organic phase was dried over Na2SO4and concentrated. The crude product was purified by chromatography on silica gel, using as eluent a mixture of hexane/tO in order of increasing polarity and thereby obtain 152 mg specified in the title compound (yield 76%).

LC-MS (method 1): tR=? 7.04 baby mortality min; m/z=443,2 [M+H]+.

Following a procedure similar to that described in example 16, but using in each case the corresponding starting compound were obtained products are shown in the following table:

ExampleConnection nameThe source connectionsLC-MS
MethodtR
(min)
m/z [M+H]+
172-[5,7-Bis-(4-forfinal)-6-(4-pyridyl)thieno[3,2-b]pyridine-3-yl]propane-2-olExample 1 18,82459,1
182-[5,7-Bis-(4-forfinal)-1-methyl-6-(4-pyridyl)imidazo[4,5-b]pyridine-2-yl]propane-2-olExample 515,32457,2
191-[5,7-Bis-(4-forfinal)-1-methyl-6-(4-pyridyl)imidazo[4,5-b]pyridine-2-yl]alanonExample 516,66441,1
202-[5,7-Bis-(4-forfinal)-1-methyl-6-(4-pyridyl)pyrrolo[3,2-b]pyridine-2-yl]propane-2-olExample 315,17456,2
211-[5,7-Bis-(4-forfinal)-1-methyl-6-(4-pyridyl)pyrrolo[3,2-b]pyridine-2-yl]alanonExample 317,08440,1

EXAMPLE 22

[4,6-Bis-(4-forfinal)-5-(4-pyridyl)furo[2,3-b]pyridine-2-yl]methanol

Specified in the title compound was obtained by following the procedure similar to that described in example 6, but the use of the Yaya as the parent compound methyl 4,6-bis-(4-forfinal)-5-(4-pyridyl)furo[2,3- b]pyridine-2-carboxylate (obtained in example 2).

LC-MS (method 1): tR=6,26 min; m/z=415,0 [M+H]+.

EXAMPLE 23

(2-Methoxyethyl)amide 4,6-bis-(4-forfinal)-5-pyridin-4-elforo[2,3-b]pyridine-2-carboxylic acid

a) 4,6-Bis-(4-forfinal)-5-pyridin-4-elforo[2,3-b]pyridine-2-carboxylic acid

Specified in the title compound was obtained by following the procedure similar to that described in example 10a but from methyl 4,6-bis-(4-forfinal)-5-(4-pyridyl)furo[2,3-b]pyridine-2-carboxylate (obtained in example 2) (yield: 95%).

LC-MS (method 3): tR=2,6 min; m/z=429 [M+H]+.

(b) 4,6-Bis-(4-forfinal)-5-pyridin-4-elforo[2,3-b]pyridine-2-carbonylchloride

To a solution of 4,6-bis-(4-forfinal)-5-pyridin-4-elforo[2,3-b]pyridine-2-carboxylic acid (0.20 g, 0.47 mmol, obtained in example 23a) in 1,2-dichloropropane (4 ml) under nitrogen atmosphere was added dropwise thionyl chloride (0,068 ml of 0.94 mmol). The mixture was heated at the boil under reflux for 1 hour in nitrogen atmosphere. Gave the mixture to cool and then concentrated. The residue was dissolved in toluene and concentrated to dryness, thus obtaining specified in the title compound (yield: 95%).

c) (2-Methoxyethyl)amide 4,6-bis-(4-forfinal)-5-pyridin-4-elforo[2,3-b]pyridine-2-carboxylic acid

To a solution of 4,6-bis-(4-forfinal)-5-pyridin-4-elforo[2,3-b]pyridin-carbonylchloride (0.05 g, 0.11 mmol, obtained in example 23b) in CH2Cl2(1 ml) was added 2-methoxyethylamine (0.05 g, of 0.68 mmol). The mixture was stirred over night at room temperature. Added CH2Cl2and washed with 3%aqueous citric acid solution (3×) and saturated solution of NaHCO3(2×). The aqueous phase was extracted with CH2Cl2(2×). The organic phase was dried over MgSO4and concentrated to dryness. The crude product was purified by chromatography on silica gel, using as eluent a mixture of heptane/EtOAc in order of increasing polarity and thereby obtain 47 mg of the desired product as a white solid (yield: 88%).

LC-MS (method 3): tR=2,47 min; m/z=486 [M+H]+.

EXAMPLES 24-26

Following a procedure similar to that described in example 23c, but using in each case the corresponding amine, obtained compounds shown in the following table:

ExampleConnection nameAminLC-MS
MethodtR
(min)
m/z [M+H]+
24Cut the MFA 4,6-bis-(4-forfinal)-5-pyridin-4-elforo[2,3- b]pyridine-2-carboxylic acid1-Propylamine32,63470
25(2-Morpholine-4-retil)amide 4,6-bis-(4-forfinal)-5-pyridin-4-elforo[2,3-b]pyridine-2-carboxylic acid2-morpholine-4-ylethylamine32,31541
26(2-piperidine-1-retil)amide 4,6-bis-(4-forfinal)-5-pyridin-4-elforo[2,3-b]pyridine-2-carboxylic acid2-piperidine-1-ylethylamine32,41539

EXAMPLE 27

(2-Hydroxyethyl)amide 4,6-bis-(4-forfinal)-5-pyridin-4-elforo[2,3-b]pyridine-2-carboxylic acid

To a solution of 4,6-bis-(4-forfinal)-5-pyridin-4-elforo[2,3-b]pyridine-2-carboxylic acid (0,058 g, 0.14 mmol, obtained in example 23a) and TEA (0,077 ml of 0.56 mmol) in CH2Cl2(2 ml) was added 2-aminoethanol (41 mg, of 0.68 mmol) and 1,3-dimethylimidazolidine (163 mg, of 0.68 mmol). The mixture was heated using microwave irradiation at 110°C for 20 minutes, After cooling, was added CH2Cl2and the mixture was washed with 0.5 N aqueous solution of HCl (3×)Vodou phase was extracted with CH 2Cl2(2×). The organic phase was dried over MgSO4and concentrated to dryness. The crude product was purified by chromatography on silica gel, using as eluent a mixture of CH2Cl2/MeOH in increasing order of polarity, and while receiving 5 mg of the desired product as a white solid (yield: 8%).

LC-MS (method 3): tR=to 2.57 min; m/z=472 [M+H]+.

EXAMPLES 28-31

Following a procedure similar to that described in example 23, but on the basis of example 3 instead of the example 2 and using in each case the appropriate amine in stage c), obtained compounds shown in the following table:

ExampleConnection nameAminVEHI
MethodtR
(min)
MS m/z [M+H]+
28(2-Methoxyethyl)amide 5,7-bis-(4-forfinal)-1-methyl-6-pyridin-4-yl-1H-pyrrolo[3,2-b]pyridine-2-carboxylic acid2-methoxy-ethylamine510,76499
29Propelled 5,7-bis-(4-forfinal)-1-methyl-6-pyridin-4-yl-1H-pyrrolo[3,2-b]pyridine-2-carboxylic acid1-Propylamine512,3483
30(2-Morpholine-4-retil)amide 5,7-bis-(4-forfinal)-1-methyl-6-pyridin-4-yl-1H-pyrrolo[3,2-b]pyridine-2-carboxylic acid2-morpholine-4-ylethylamine58,29554
31(2-piperidine-1-retil)amide 5,7-bis-(4-forfinal)-1-methyl-6-pyridin-4-yl-1H-pyrrolo[3,2-b]pyridine-2-carboxylic acid2-piperidine-1-ylethylamine59,38552

EXAMPLE 32

[5,7-bis-(4-forfinal)-1-methyl-6-pyridin-4-yl-1H-pyrrolo[3,2-b]pyridine-2-ylmethyl]-(2-methoxyethyl)Amin

a) 5,7-bis-(4-forfinal)-1-methyl-6-pyridin-4-yl-1H-pyrrolo[3,2-b]pyridine-2-carbaldehyde

To a solution of [5,7-bis-(4-forfinal)-1-methyl-6-(4-pyridyl)pyrrolo[3,2-b]pyridine-2-yl]methanol (0,445 g, 1.04 mmol, obtained in example 6) and TEA (0,725 ml, 5.2 mmol) in DMSO (3 ml) under nitrogen atmosphere was added pyridine complex-SO30,496 g, of 3.12 mmol). The mixture was stirred at room temperature for 1 hour. The mixture is then poured into ice and added EtOAc. The organic phase is washed with water (2×). The aqueous phase was extracted with EtOAc (2×). The organic phase was dried over MgSO4and concentrated to dryness, thus obtaining 395 mg of the desired product as a white solid (yield: 90%).

LC-MS (method 3): tR=2,63 min; m/z=426 [M+H]+.

b) [5,7-bis-(4-forfinal)-1-methyl-6-pyridin-4-yl-1H-pyrrolo[3,2-b]pyridine-2-ylmethyl]-(2-methoxyethyl)Amin

To a solution of 5,7-bis-(4-forfinal)-1-methyl-6-pyridin-4-yl-1N-pyrrolo[3,2-b]pyridine-2-carbaldehyde (0,099 g, 0.23 mmol, obtained in example 32a) in CH2Cl2(1 ml) at room temperature was added 2-methoxyethylamine (0.10 ml, 1.15 mmol). Acetic acid brought the pH of the mixture to pH=6 and the mixture was stirred for 2 hours at room temperature. Then was added Na(OAc)3BH (0,244 g, 1.15 mmol) and stirred the reaction mixture at room temperature over night. Was added a saturated aqueous solution of NaHCO3and EtOAc. The organic phase was washed with a saturated aqueous solution of Na2CO3(2×). The aqueous phase was extracted with EtOAc (2×). The organic phase was dried over MgSO4and concentrated to dryness. The crude product was purified by chromatography on silica gel, using as eluent a mixture of CH2 Cl2/MeOH in increasing order of polarity and thereby obtain 49 mg of the desired product as a white solid (yield: 44%).

LC-MS (method 3): tR=2,41 min; m/z=485 [M+H]+.

EXAMPLE 33

[5,7-bis-(4-forfinal)-1-methyl-6-pyridin-4-yl-1H-pyrrolo[3,2-b]pyridine-2-ylmethyl]cyclopropanemethylamine

Specified in the title compound as a white solid (58 mg, yield: 52%) was obtained by following the procedure similar to that described in example 32b, but using instead 2-methoxyethylamineC-cyclopropanemethylamine.

LC-MS (method 3): tR=2,40 min; m/z=481 [M+H]+.

EXAMPLES 34 and 35

Methyl ester {[5,7-bis-(4-forfinal)-1-methyl-6-pyridin-4-yl-1H-pyrrolo[3,2-b]pyridine-2-ylmethyl]amino}acetic acid (34)

Methyl ester {[5,7-bis-(4-forfinal)-1-methyl-6-pyridin-4-yl-1H-pyrrolo[3,2-b]pyridine-2-ylmethyl]-N-ethylamino}acetic acid (35)

Specified in the title compounds as white solids were obtained by following the procedure similar to that described in example 32b, but using instead 2-methoxyethylamine methyl ester aminouksusnoy acid.

Example 34: 9 mg, yield: 8%

LC-MS (method 3): tR=2,39 min; m/z=499 [M+H]+.

Example 35: 8 mg, yield: 7%.

LC-MS (method 3): tR=2,45 min; m/z=527 [M+H]+.

EXAMPLE 36

[5,7-the IP-(4-forfinal)-1-methyl-6-pyridin-4-yl-1 N-pyrrolo[3,2-b]pyridine-2-ylmethyl]Propylamine

Specified in the title compound as a white solid (6 mg, yield: 29%) was obtained by following the procedure similar to that described in example 32b, but using instead 2-methoxyethylamine 1-Propylamine.

LC-MS (method 3): tR=2,41 min; m/z=469 [M+H]+.

EXAMPLE 37

5,7-bis-(4-forfinal)-1-methyl-6-pyridin-4-yl-1H-pyrrolo[3,2-b]pyridine

To a solution of [5,7-bis-(4-forfinal)-1-methyl-6-(4-pyridyl)pyrrolo[3,2-b]pyridine-2-yl]methanol (0.05 g, 0.11 mmol, obtained in example 6) in dioxane (1 ml) was added KOtBu (0.025 g, 0.22 mmol) and 4-(2-chloroethyl)morpholine·HCl (0,020 mg, 0.11 mmol) and stirred the reaction mixture at room temperature over night. The mixture was acidified with an aqueous solution of HCl to pH=7 and then added EtOAc. The organic phase was washed with a saturated aqueous solution of Na2CO3(3×). The aqueous phase was extracted with EtOAc (2×). The organic phase was dried over MgSO4and concentrated to dryness. The crude product was purified by chromatography on silica gel, using as eluent a mixture of CH2Cl2/MeOH in increasing order of polarity, and while receiving 8 mg of the desired product as a white solid (yield: 19%).

LC-MS (method 3): tR=to 2.29 min; m/z=398 [M+H]+.

EXAMPLE 38

[5,7-bis-(4-forfinal)-1-methyl-6-pyridin-4-yl-1 -imidazo[4,5-b]pyridine-2-yl]morpholine-4-ylmethanol

To a solution of ethyl 5,7-bis-(4-forfinal)-1-methyl-6-(4-pyridyl)imidazo[4,5-b]pyridine-2-carboxylate (60 mg, 0.13 mmol, obtained in example 5) in EtOH (2 ml) was added morpholine (330 μl, a 3.83 mmol). The resulting mixture was heated to 150°C for 20 min using microwave irradiation. After evaporation of the solvent the crude product was purified preparative HPLC and was liofilizovane, while receiving specified in the title compound as a white solid (yield: 20%).

HPLC (method 6): tR=10,87 min, MS: m/z=512 [M+H]+.

EXAMPLE 39

Methyl ester 5,7-bis-(4-forfinal)-6-pyridin-4-yl-1H-pyrazolo[4,3-b]pyridine-3-carboxylic acid

5 mg indicated in the title compounds as white solids (yield: 5%) was obtained by following the procedure similar to that described in example 1, but using instead of methyl 4-aminothiophene-3-carboxylate methyl ester 4-amino-1H-pyrazole-3-carboxylic acid (obtained in reference example 7) and ethanol as solvent.

HPLC (method 4): tR=6,17 min, MS: m/z=443 [M+H]+.

EXAMPLE 40

Cyclopropylmethyl-{4-[6-(4-forfinal)-3-methylisoxazole[5,4-b]pyridine-5-yl]pyrimidine-2-yl}Amin

a) 6-(4-Forfinal)-3-methyl-5-(2-methylsulfonylamino-4-yl)isoxazole[5,4-b]pyridine

To a solution of 1-(4-forfinal)-2-(2-methylsulfonylamino-4-yl)propenone (1.08 g, 3.93 mmol, obtained in reference example 5c) and 3-methylisoxazol-5-ylamine (0,42 g, 4,32 mmol) in EtOH (30 ml) was added 37% aqueous HCl solution (0,113 ml, 1.18 mmol). The reaction mixture was stirred for 2 days at room temperature. Then added nitrate ammonium cerium (IV)to complete the reaction. The reaction mixture was washed with saturated aqueous NaHCO3(3×). The aqueous phase was extracted with EtOAc. The organic phase was dried over MgSO4and concentrated to dryness. The crude product was purified by chromatography on silica gel, using as eluent a mixture of heptane/EtOAc in order of increasing polarity, and while receiving 523 mg of the desired product as a white solid (yield: 38%).

LC-MS (method 3): tR=3,03 min; m/z=353 [M+H]+.

b) 6-(4-Forfinal)-5-(2-methanesulfonamido-4-yl)-3-methylisoxazole[5,4-b]pyridine

To a solution of 6-(4-forfinal)-3-methyl-5-(2-methylsulfonylamino-4-yl)isoxazole[5,4-b]pyridine (0.1 g, 0.28 mmol) in MeOH (5 ml) was added Oxon®(0.87 g, of 1.42 mmol) in water (5 ml). The mixture was stirred for 1 hour at room temperature. After evaporation of methanol was added EtOAc and saturated aqueous solution of NaHCO3. The organic phase is washed with saturated aqueous NaHCO3(2×). The aqueous phase is ex who was regionali EtOAc (2×). The organic phase was dried over MgSO4and concentrated to dryness. The crude product was purified by chromatography on silica gel, using as eluent a mixture of CH2Cl2/MeOH in increasing order of polarity and thereby obtain 47 mg of the desired product as a white solid (yield: 56%).

LC-MS (method 3): tR=2,82 min; m/z=385 [M+H]+.

(C) Cyclopropylmethyl-{4-[6-(4-forfinal)-3-methylisoxazole[5,4-b]pyridine-5-yl]pyrimidine-2-yl}Amin

To a solution of 6-(4-forfinal)-5-(2-methanesulfonamido-4-yl)-3-methylisoxazole[5,4-b]pyridine (of 0.045 g, 0.12 mmol) in THF (0.5 ml) was addedC-cyclopropanemethylamine (0,052 ml of 0.60 mmol). The reaction mixture was heated at 50°C for 2.5 hours. The organic phase is washed with water and saturated salt solution (2×). The aqueous phase was extracted with EtOAc. The organic phase was dried over MgSO4and concentrated to dryness. The crude product was purified by chromatography on silica gel, using as eluent a mixture of heptane/EtOAc in order of increasing polarity and thereby obtain 41 mg of the desired product as a white solid (yield: 91%).

LC-MS (method 3): tR=2,82 min; m/z=376 [M+H]+.

EXAMPLES 41-42

Following a procedure similar to that described in example 40c, but using in each case the corresponding amine, was obtained from the organisations, in the following table:

ExampleConnection nameAminLC-MS
MethodtR
(min)
m/z [M+H]+
41{4-[6-(4-Forfinal)-3-methylisoxazole[5,4-b]pyridine-5-yl]pyrimidine-2-yl}-(3-methoxypropyl)Amin3-methoxy-Propylamine32,72394
42(S)-{4-[6-(4-Forfinal)-3-methylisoxazole[5,4-b]pyridine-5-yl]pyrimidine-2-yl}-(1-phenylethyl)amine(S)-1-phenylethyl-amine33,01426

EXAMPLE 43

Cyclopropylmethyl-{4-[6-(4-forfinal)-3-methylisothiazolone[5,4-b]pyridine-5-yl]pyrimidine-2-yl}Amin

a) 6-(4-Forfinal)-3-methyl-5-(2-methylsulfonylamino-4-yl)isothiazole[5,4-b]pyridine

Specified in the title compound as a white solid (202 mg, yield: 31%) was obtained by following the procedure similar to that, opican the th in example 40a, but instead of applying 3-methylisoxazol-5-ylamine 3-metalization-5-ylamine.

LC-MS (method 3): tR=2,96 min; m/z=369 [M+H]+.

b) 6-(4-Forfinal)-5-(2-methanesulfonamido-4-yl)-3-methylisothiazolone[5,4-b]pyridine

Specified in the title compound as a white solid (204 mg, yield: 93%) was obtained by following the procedure similar to that described in example 40b, but using instead of 6-(4-forfinal)-3-methyl-5-(2-methylsulfonylamino-4-yl)isoxazole[5,4-b]pyridine 6-(4-forfinal)-3-methyl-5-(2-methylsulfonylamino-4-yl)isothiazole[5,4-b]pyridine.

MS: m/z=401 [M+H]+.

c) Cyclopropylmethyl-{4-[6-(4-forfinal)-3-methylisothiazolone[5,4-b]pyridine-5-yl]pyrimidine-2-yl}Amin

Specified in the title compound as a white solid (44 mg, yield: 66%) was obtained by following the procedure similar to that described in example 40c, but using instead of 6-(4-forfinal)-5-(2-methanesulfonamido-4-yl)-3-methylisoxazole[5,4-b]pyridine 6-(4-forfinal)-5-(2-methanesulfonamido-4-yl)-3-methylisothiazolone[5,4-b]pyridine.

LC-MS (method 3): tR=2,90 min; m/z=392 [M+H]+.

EXAMPLES 44-45

Following a procedure similar to that described in example 43, but using in each case at the stage (c) the appropriate amine, obtained compounds shown in the following table:

ExampleConnection nameAminLC-MS
MethodtR
(min)
m/z [M+H]+
44{4-[6-(4-Forfinal)-3-methylisothiazolone[5,4-b]pyridine-5-yl]pyrimidine-2-yl}-(3-methoxypropyl)Amin3-methoxy-Propylamine32,79410
45(S)-{4-[6-(4-Forfinal)-3-methylisothiazolone[5,4-b]pyridine-5-yl]pyrimidine-2-yl}-(1-phenylethyl)amine(S)-1-phenylethyl-amine33,11442

EXAMPLE 46

Cyclopropylmethyl-{4-[5-(4-methoxyphenyl)-1H-pyrrolo[3,2-b]pyridine-6-yl]pyrimidine-2-yl}Amin

a) 5-(4-Methoxyphenyl)-6-(2-methylsulfonylamino-4-yl)-1H-pyrrolo[3,2-b]pyridine

Specified in the title compound as a white solid (581 mg, yield: 86%) was obtained by following the procedure similar to that described in example 40a, but using instead of 3-methylisoxazol-5-ylamine 1H-pyrrol-alamin and instead reference example 5, reference example 6.

MS: m/z=385,2 [M+H]+.

b) 6-(2-Methanesulfonamido-4-yl)-5-(4-methoxyphenyl)-1H-pyrrolo[3,2-b]pyridine

Specified in the title compound as a white solid (154 mg, yield: 49%) was obtained by following the procedure similar to that described in example 40b, but using instead of 6-(4-forfinal)-3-methyl-5-(2-methylsulfonylamino-4-yl)isoxazole[5,4-b]pyridine 5-(4-methoxyphenyl)-6-(2-methylsulfonylamino-4-yl)-1N-pyrrolo[3,2-b]pyridine.

MS: m/z=417,2 [M+H]+.

c) Cyclopropylmethyl-{4-[5-(4-methoxyphenyl)-1H-pyrrolo[3,2-b]pyridine-6-yl]pyrimidine-2-yl}Amin

Specified in the title compound as a white solid (4.5 mg, yield: 25%) was obtained by following the procedure similar to that described in example 40c, but using instead of 6-(4-forfinal)-5-(2-methanesulfonamido-4-yl)-3-methylisoxazole[5,4-b]pyridine 6-(2-methanesulfonamido-4-yl)-5-(4-methoxyphenyl)-1H-pyrrolo[3,2-b]pyridine.

LC-MS (method 3): tR=2,37 min; m/z=372 [M+H]+.

EXAMPLE 47

(S)-{4-[5-(4-methoxyphenyl)-1H-pyrrolo[3,2-b]pyridine-6-yl]pyrimidine-2-yl}-(1-phenylethyl)amine

Specified in the title compound as a white solid (2 mg, yield: 12%) was obtained by following the procedure similar to that described in example 46, but using instead ofC-cyclopropanemethylamine (S-1-phenylethylamine.

LC-MS (method 3): tR=2,56 min; m/z=422,2 [M+H]+.

EXAMPLE 48

6-(4-Forfinal)-4-(2-forfinal)-3-methyl-5-pyridin-4-isoxazole[5,4-b]pyridine

A solution of 1-(4-forfinal)-2-pyridine-4-ratanana (250 mg, of 1.16 mmol), 2-forventelige (125 μl, of 1.16 mmol) and 3-methylisoxazol-5-amine (125 mg, 1.28 mmol) in EtOH was stirred at 45°C for 65 hours. After cooling to room temperature, added water and nitrate of ammonium cerium (IV) (636 mg, of 1.16 mmol) and further stirred the reaction mixture for 1 hour. The mixture was diluted with EtOAc and washed with saturated aqueous NaHCO3. The organic solvent was removed in vacuum and the residue was purified by chromatography on silica gel, using as eluent a mixture of heptane/EtOAc in order of increasing polarity and thereby obtain 264 mg of the desired product as yellow solid substance (yield: 57%).

HPLC (method 5): tR=15,81 min, MS: m/z=400 [M+H]+.

EXAMPLE 49

4,6-Bis-(4-forfinal)-3-methyl-5-pyridin-4-ilizational[5,4-b]pyridine

Following a procedure similar to that described in example 48, but using instead 2-forventelige 4-forbindelse and instead of 3-methylisoxazol-5-amine hydrochloride 5-amino-3-methylisothiazolone received 139 mg specified in the title compound as a pale yellow solid (yield: 29%).

HPLC (method 5): tR=16,34 is in, MS: m/z=416 [M+H]+.

EXAMPLE 50

4-(2-forfinal)-6-(4-forfinal)-3-methyl-5-pyridin-4-ilizational[5,4-b]pyridine

Following a procedure similar to that described in example 48, but using instead of 3-methylisoxazol-5-amine hydrochloride 5-amino-3-methylisothiazolone, received 57 mg specified in the title compound as a pale yellow solid (yield: 12%).

HPLC (method 5): tR=the value of 16,81 min, MS: m/z=416 [M+H]+.

EXAMPLE 51

3-methyl-5-pyridin-4-yl-6-(3-triptoreline)isoxazole[3,4-b]pyridine

To a solution of 2-pyridin-4-yl-1-(3-triptoreline)ethanone (50 mg, 0.2 mmol, obtained in reference example 9b) and complex tert-butyl ester (4-formyl-5-methylisoxazol-3-yl)carbamino acid (106 mg, 0.47 mmol, obtained in reference example 8b) in EtOH (1 ml) was added piperidine (5 ml) and acetic acid (5 μl). The reaction mixture was heated using microwave irradiation at 155°C for 30 minutes added piperidine (10 μl) and acetic acid (10 μm) and again heated the reaction mixture for 30 min at 155°C. Then the reaction mixture was poured into water and EtOAc. The organic layer was dried over Na2SO4and concentrated to dryness. The residue was purified by chromatography on silica gel, using as eluent a mixture of heptane/EtOAc in order of increasing polarity, and while receiving 4 mg required from the organisations (yield: 6%).

HPLC (method 5): tR=13,37 min; MS: m/z=356 [M+H]+.

EXAMPLE 52

Cyclopropylmethyl-{4-[5-(4-forfinal)-2-methylthiazole[5,4-b]pyridine-6-yl]pyrimidine-2-yl}Amin

a) 5-(4-Forfinal)-2-methyl-6-(2-methylsulfonylamino-4-yl)thiazolo[5,4-b]pyridine

To a solution ofN-[2-chloro-6-(4-forfinal)-5-(2-methylsulfonylamino-4-yl)pyridine-3-yl]ndimethylacetamide (0.15 g, 0.38 mmol, obtained in reference example 10e) in pyridine (1.5 ml) was added at room temperature and in an atmosphere of nitrogen pentasulfide phosphorus (0,22 g, 0,99 mmol). The mixture was heated to 120°C and was stirred for 2 hours. Then the mixture was cooled to room temperature and added water. The aqueous phase was extracted with dichloromethane (2×) and the combined organic phases are washed with 2 M HCl solution (2×) and saturated salt solution (1×), dried over Na2SO4and concentrated to dryness. The crude product was purified by chromatography on silica gel, using as eluent a mixture of heptane/EtOAc in order of increasing polarity and thereby obtain 64 mg specified in the title compound (yield: 45%).

MS: m/z=369 [M+H]+.

b) 5-(4-Forfinal)-6-(2-methanesulfonamido-4-yl)-2-methylthiazole[5,4-b]pyridine

Following a procedure similar to that described in example 40b, but using instead of 6-(4-forfinal)-3-methyl-5-(2-methylsulfonylamino-4-yl)isoxazole[5,4-b]PI is Idina 5-(4-forfinal)-2-methyl-6-(2-methylsulfonylamino-4-yl)thiazolo[5,4- b]pyridine was obtained is listed in the title compound as a white solid (52 mg, yield: 75%).

MS: m/z=401 [M+H]+.

c) Cyclopropylmethyl-{4-[5-(4-forfinal)-2-methylthiazole[5,4-b]pyridine-6-yl]pyrimidine-2-yl}Amin

Following a procedure similar to that described in example 40c, but using instead of 6-(4-forfinal)-5-(2-methanesulfonamido-4-yl)-3-methylisoxazole[5,4-b]pyridine 5-(4-forfinal)-6-(2-methanesulfonamido-4-yl)-2-methylthiazole[5,4-b]pyridine was obtained is listed in the title compound in solid form white (10 mg, yield: 20%).

HPLC (method 5): tR=17,41 min MS: m/z=392 [M+H]+.

EXAMPLE 53

5,7-Bis-(4-forfinal)-6-pyridin-4-yl-1H-pyrazolo[4,3-b]pyridine

To a solution of complex methyl ester 5,7-bis-(4-forfinal)-6-pyridin-4-yl-1H-pyrazolo[4,3-b]pyridine-3-carboxylic acid (100 mg, 0.23 mmol, obtained in example 39) in NMP (1 ml) was added 2 N HCl (50 ml). The resulting mixture was heated at C for 20 minutes using microwave irradiation. The reaction mixture was poured into water and was extracted with EtOAc. The organic layer was dried over Na2SO4and concentrated. The residue was purified preparative HPLC, while receiving 16 mg specified in the connection header as not quite white solids (yield: 18%).

HPLC (method 5): tR=11,25 min MS: m/z=385 [M+H]+/sup> .

EXAMPLE 54

(2-Hydroxyethyl)amide 5,7-bis-(4-forfinal)-6-pyridin-4-yl-1H-pyrazolo[4,3-b]pyridine-3-carboxylic acid

The complex solution of methyl ether 5,7-bis-(4-forfinal)-6-pyridin-4-yl-1H-pyrazolo[4,3-b]pyridine-3-carboxylic acid (100 mg, 0.23 mmol, obtained in example 39) in 2-aminoethanol (1 ml) was heated at 150°C for 30 minutes using microwave irradiation. The reaction mixture was poured into water and was extracted with EtOAc. The organic layer was dried over Na2SO4and concentrated in vacuum. The residue was purified preparative HPLC, while receiving 42 mg specified in the connection header as not quite white solids (yield: 40%).

HPLC (method 5): tR=minutes of 9.30 MS: m/z=472 [M+H]+.

EXAMPLE 55

6-(4-Forfinal)-3-methyl-5-pyridin-4-isoxazole[3,4-b]pyridine

Following a procedure similar to that described in example 51, but using instead 2-pyridin-4-yl-1-(3-triptoreline)ethanone (obtained in reference example 9b) 1-(4-forfinal)-2-(4-pyridyl)alanon (obtained in reference example 1)were specified in the title compound as a white solid (11 mg, yield: 5%).

HPLC (method 5): tR=to 9.91 min MS: m/z=306 [M+H]+.

EXAMPLE 56

(S)-{4-[5-(4-forfinal)-2-methylthiazole[5,4-b]pyridine-6-yl]pyrimidine-2-yl}-(1-phenylethyl)amine

SL is blowing procedure similar to the procedure described in example 52c, but using instead ofC-cyclopropanemethylamine (S)-1-phenylethylamine, got mentioned in the title compound as a white solid (3 mg, yield: 6%).

HPLC (method 5): tR=20,46 min MS: m/z=442 [M+H]+.

EXAMPLE 57

Biological tests

Inhibition of enzyme activity of p38α

Stock solutions of the compounds in 100% DMSO were first diluted in DMSO to a concentration in the range from 1×10-3to 3.2×10-8M and then further diluted with buffer for analysis of kinase activity (10 mm Tris-HCl, pH to 7.2, 10 mm MgCl2, 0.01% tween-20, 0.05% of NaN3, 1 mm dithiothreitol) to the concentration in the range from 4×10-5to 1.3×10-9M. 5 μl of a Solution of each compound was transferred into a 384-well black tablet Optiplate (Packard, 6007279), followed by adding 5 μl of ATP (Boehringer, 519987), 5 μl of peptide substrate of EGFR (the receptor for epidermal growth factor), labeled with fluorescein, and 5 ál of active p38α kinase (GST-tagged protein corresponding to full-sized human p38α kinase, expressed in E.coli production Upstate, 14-251), and all of this was diluted with buffer for analysis of kinase activity (see final concentration in table 1). The mixture is incubated for 2 hours at room temperature (RT). The reaction was stopped by adding 60 μl of binding re the Ghent IMAP, which was 400-fold diluted binding buffer IMAP (stock solution of 5-fold diluted with Milli Q). After incubation for 30 minutes at room temperature was measured FP on multimode fluorescent reader tablet Analyst™ (Molecular Devices) at a wavelength of excitation 485 nm and the wavelength of emission of 530 nm (1 sec/well).

Table 1
Test conditions
Kinase
(from Upstate)
The final concentrationSubstrateThe final concentrationThe final concentration of ATP
P38α/SAPK2a, active0,30 Ed./mlLVEPLTPSGEAPNQK-(Fl)240 nm20 mm

Processing of data was performed as follows: the obtained effects in percentage was calculated on the basis of experiments, assuming a maximum inhibitory effect of the sample without addition of the enzyme p38 and minimum inhibitory effects of the sample with the addition of the enzyme p38. In each experiment, the concentrations of individual compounds were tested in two parallel samples and calculated the effect in percent for each of the concentrations.

In the above connection test all of the examples showed a greater than 50% inhibition at a concentration of 10 μm. In the above test the compounds in the examples 1, 2, 3, 5, 6, 7, 10, 12, 13, 14, 16, 18, 19, 20, 21, 22, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 39, 40, 41, 42, 43, 44, 45, 46, 47, 52, 53, 54 and 56 showed a greater than 50% inhibition at a concentration of 1 μm.

1. The compound of General formula I

where And represents C or N;
B, D and E independently represent CR4, NR5N, O or S;
and the ring containing groups a, b, D, E, choose from tanila, furan, imidazole, isoxazol, isothiazole, thiazole, pyrrole, pyrazole;
the following conditions are met:
b) when a represents N, none, D, E may not represent O or S; and
c) when a represents C, represents CR4and one of D or E represents N or NR5while the other of D or F may not represent NR5or N;
G represents N or C;
R1represents one or more substituents selected from H, Ra, halogen, -HE-ORa;
R2represents one or more substituents selected from H, halogen and C1-6-alkyl, and, in addition, one of the substituents R2may also represent-ORb', -NRb'Rb', -SRb', -SORb, -SO2Rb , -SO2NRb'Rb';
R3represents N or
Su selected from phenyl, optionally substituted by one or more substituents selected from Rcwhere Rcindependently represents halogen, -ORg'where Rg'independently represents a group Rgwhere Rgrepresents a C1-6-alkyl;
each R4independently represents H, Re, halogen,
-CORe', -CO2Re', -CONRe'Re', -NRe'Re';
R5independently represents H, Re, -CORe, -CONReRe, -SOReor-SO2Re;
each Raindependently represents a C1-6-alkyl or halogen-C1-6-alkyl;
each Rbindependently represents a C1-6-alkyl, optionally substituted by one or more substituents selected from Rdand Rf;
each Rb'independently represents H or Rb;
each Rcindependently represents halogen, -ORg', -CONRg'Rg', -NRg'Rg';
Rdis a su, optionally substituted by one or more substituents Rf;
each Reindependently represents a C1-6-alkyl, optionally substituted by one or more substituents selected from Rcand who the*, or Reis a su, where any of the groups su or su* optionally can be substituted by one or more substituents selected from Rcand Rg;
each Re'independently represents H or Re;
each Rfindependently represents halogen, -ORh',
-CO2Rh';
each Rgindependently represents Rdor C1-6-alkyl, optionally substituted by one or more substituents selected from Rdand Rf;
each Rg'independently represents H or Rg;
each Rhindependently represents a C1-6-alkyl, halogen-C1-6-alkyl or hydroxy-C1-6-alkyl;
each Rh'independently represents H or Rh;
Su or su* in the above definitions represents a partially saturated, saturated or aromatic 3-7 membered monocyclic carbocyclic ring, which optionally contains 1 to 2 heteroatoms selected from N and O, and where the specified ring or rings may be connected with the rest of the molecule through a carbon atom or a nitrogen atom;
or its pharmaceutically acceptable salt.

2. The compound according to claim 1, in which R1represents one or more substituents selected from H, Rahalogen and-ORa.

3. Connect the tion according to claim 2, in which R1represents one or two substituent selected from halogen, halogen-C1-6-alkyl and C1-6-alkoxy.

4. The compound according to any one of claims 1 to 3, in which a is a C.

5. The compound according to claim 1, in which

represents a group selected from groups (a)-(h)



6. The compound according to claim 1, in which R4independently represents H, Re-CORe', CO2Re', -CONRe'Re'or-NRe'Re'.

7. The compound according to claim 1, in which R5independently represents H or Re.

8. The connection according to claim 7, in which R5independently represents N or C1-6-alkyl.

9. The compound according to claim 1, in which R2represents one Deputy, selected from H, halogen, C1-6-alkyl, -ORb'and NRb'Rb'.

10. The compound according to claim 1, in which G represents C and R2represents N.

11. The compound according to claim 1, in which G represents N, R2is an-otherband is located in position 2 of the pyrimidine cycle and Rbis a Csub> 1-6-alkyl, substituted by one Deputy, selected from su and-ORh'.

12. The connection of claim 10, in which R3represents phenyl, which optionally may be substituted by one or more halogen atoms.

13. Connection by claim 11, in which R3represents H.

14. The compound according to claim 1, selected from
methyl 5,7-bis-(4-forfinal)-6-(4-pyridyl)thieno[3,2-b]pyridine-3-carboxylate;
methyl 4,6-bis-(4-forfinal)-5-(4-pyridyl)furo[2,3-b]pyridine-2-carboxylate;
methyl 5,7-bis-(4-forfinal)-1-methyl-6-(4-pyridyl)pyrrolo[3,2-b]pyridine-2-carboxylate;
4,6-bis-(4-forfinal)-3-methyl-5-(4-pyridyl)isoxazole[5,4-b]pyridine;
ethyl 5,7-bis-(4-forfinal)-1-methyl-6-(4-pyridyl)imidazo[4,5-b]pyridine-2-carboxylate;
[5,7-bis-(4-forfinal)-1-methyl-6-(4-pyridyl)pyrrolo[3,2-b]pyridine-2-yl]methanol;
[5,7-bis-(4-forfinal)-1-methyl-6-(4-pyridyl)imidazo[4,5-b]pyridine-2-yl]methanol;
5,7-bis-(4-forfinal)-2-methyl-6-(4-pyridyl)pyrazolo[1,5-a]pyrimidine;
2-methyl-5,7-diphenyl-6-(4-pyridyl)pyrazolo[1,5-a]pyrimidine;
5,7-bis-(4-forfinal)-1-methyl-6-(4-pyridyl)imidazo[4,5-b]pyridine;
5,7-bis-(4-forfinal)-N-(2-hydroxyethyl)-6-(4-pyridyl)thieno[3,2-b]pyridine-3-carboxamide;
5,7-bis-(4-forfinal)-1-methyl-6-(4-pyridyl)pyrrolo[3,2-b]pyridine-2-carboxamide;
5,7-bis-(4-forfinal)-N-(2-hydroxyethyl)-1-methyl-6-(4-pyridyl)pyrrolo[3,2-b] pyridine-2-carboxamide;
[5,7-bis-(4-forfinal)-1-methyl-6-(4-pyridyl)Pyrrhus is lo[3,2-b]pyridine-2-yl]morpholine-4-ylmethanone;
3-amino-5,7-bis-(4-forfinal)-6-(4-pyridyl)thieno[3,2-b]pyridine;
2-[4,6-bis-(4-forfinal)-5-(4-pyridyl)furo[2,3-b]pyridine-2-yl]propane-2-ol;
2-[5,7-bis-(4-forfinal)-6-(4-pyridyl)thieno[3,2-b]pyridine-3-yl]propane-2-ol;
2-[5,7-bis-(4-forfinal)-1-methyl-6-(4-pyridyl)imidazo[4,5-b]pyridine-2-yl]propane-2-ol;
1-[5,7-bis-(4-forfinal)-1-methyl-6-(4-pyridyl)imidazo[4,5-b]pyridine-2-yl]ethanone;
2-[5,7-bis-(4-forfinal)-1-methyl-6-(4-pyridyl)pyrrolo[3,2-b]pyridine-2-yl]propane-2-ol;
1-[5,7-bis-(4-forfinal)-1-methyl-6-(4-pyridyl)pyrrolo[3,2-b]pyridine-2-yl]ethanone;
[4,6-bis-(4-forfinal)-5-(4-pyridyl)furo[2,3-b]pyridine-2-yl]methanol;
(2-methoxyethyl)amide 4,6-bis-(4-forfinal)-5-pyridin-4-elforo[2,3-b]pyridine-2-carboxylic acid;
propylamide 4,6-bis-(4-forfinal)-5-pyridin-4-elforo[2,3-b]pyridine-2-carboxylic acid;
(2-morpholine-4-retil)amide 4,6-bis-(4-forfinal)-5-pyridin-4-elforo[2,3-b]pyridine-2-carboxylic acid;
(2-piperidine-1-retil)amide 4,6-bis-(4-forfinal)-5-pyridin-4-elforo[2,3-b]pyridine-2-carboxylic acid;
(2-hydroxyethyl)amide 4,6-bis-(4-forfinal)-5-pyridin-4-elforo [2,3-b]pyridine-2-carboxylic acid;
(2-methoxyethyl)amide 5,7-bis-(4-forfinal)-1-methyl-6-pyridin-4-yl-1H-pyrrolo[3,2-b] pyridine-2-carboxylic acid;
propylamide 5,7-bis-(4-forfinal)-1-methyl-6-pyridin-4-yl-1H-pyrrolo [3,2-b] pyridine-2-carboxylic acid;
(2-morpholine-4-retil)amide 5,7-bis-(4-forfinal)-1-methyl-6-pyridin-4-yl-1H-pyrrolo[3,2-b]pyridi the-2-carboxylic acid;
(2-piperidine-1-retil)amide 5,7-bis-(4-forfinal)-1-methyl-6-pyridin-4-yl-1H-pyrrolo[3,2-b]pyridine-2-carboxylic acid;
[5,7-bis-(4-forfinal)-1-methyl-6-pyridin-4-yl-1H-pyrrolo[3,2-b]pyridine-2-ylmethyl]-(2-methoxyethyl)amine;
[5,7-bis-(4-forfinal)-1-methyl-6-pyridin-4-yl-1H-pyrrolo[3,2-b]pyridine-2-ylmethyl]cyclopropanemethylamine;
difficult methyl ester {[5,7-bis-(4-forfinal)-1-methyl-6-pyridin-4-yl-1H-pyrrolo[3,2-b]pyridine-2-ylmethyl]amino}acetic acid;
difficult methyl ester {[5,7-bis-(4-forfinal)-1-methyl-6-pyridin-4-yl-1H-pyrrolo[3,2-b]pyridine-2-ylmethyl]-N-ethylamino}acetic acid;
[5,7-bis-(4-forfinal)-1-methyl-6-pyridin-4-yl-1H-pyrrolo[3,2-b]pyridine-2-ylmethyl]Propylamine;
5,7-bis-(4-forfinal)-1-methyl-6-pyridin-4-yl-1H-pyrrolo[3,2-b]pyridine;
[5,7-bis-(4-forfinal)-1-methyl-6-pyridin-4-yl-1H-imidazo[4,5-b]pyridine-2-yl] morpholine-4-ylmethanone;
difficult methyl ester 5,7-bis-(4-forfinal)-6-pyridin-4-yl-1H-pyrazolo[4,3-b]pyridine-3-carboxylic acid;
cyclopropylmethyl-{4-[6-(4-forfinal)-3-methylisoxazole[5,4-b]pyridine-5-yl]pyrimidine-2-yl}amine;
{4-[6-(4-forfinal)-3-methylisoxazole[5,4-b]pyridine-5-yl]pyrimidine-2-yl}-(3-methoxypropyl)amine;
(S)-{4-[6-(4-forfinal)-3-methylisoxazole[5,4-b]pyridine-5-yl]pyrimidine-2-yl}-(1-phenylethyl)amine;
cyclopropylmethyl-{4-[6-(4-forfinal)-3-methylisothiazolone[5,4-b]pyridine-5-yl]pyrimidine-2-yl} amine;
{4-[6-(4-forfinal)-3-methylisothiazolone[5,4-b]pyridi the-5-yl]pyrimidine-2-yl}-(3-methoxypropyl)amine;
(S)-{4-[6-(4-forfinal)-3-methylisothiazolone[5,4-b]pyridine-5-yl]pyrimidine-2-yl}-(1-phenylethyl)amine;
cyclopropylmethyl-{4-[5-(4-methoxyphenyl)-1H-pyrrolo[3,2-b]pyridine-6-yl]pyrimidine-2-yl}amine;
(S)-4-[5-(4-methoxyphenyl)-1H-pyrrolo[3,2-b]pyridine-6-yl]pyrimidine-2-yl}-(1-phenylethyl)amine;
6-(4-forfinal)-4-(2-forfinal)-3-methyl-5-pyridin-4-isoxazole[5,4-b]pyridine;
4,6-bis-(4-forfinal)-3-methyl-5-pyridin-4-ilizational[5,4-b]pyridine;
4-(2-forfinal)-6-(4-forfinal)-3-methyl-5-pyridin-4-ilizational[5,4-b]pyridine;
3-methyl-5-pyridin-4-yl-6-(3-triptoreline)isoxazole[3,4-b]pyridine;
cyclopropylmethyl-{4-[5-(4-forfinal)-2-methylthiazole[5,4-b]pyridin-6-yl]pyrimidine-2-yl}amine;
5,7-bis-(4-forfinal)-6-pyridin-4-yl-1H-pyrazolo[4,3-b]pyridine;
(2-hydroxyethyl)amide 5,7-bis-(4-forfinal)-6-pyridin-4-yl-1H-pyrazolo[4,3-b]pyridine-3-carboxylic acid;
6-(4-forfinal)-3-methyl-5-pyridin-4-isoxazole[3,4-b]pyridine; and
(S)-{4-[5-(4-forfinal)-2-methylthiazole[5,4-b]pyridin-6-yl]pyrimidine-2-yl}-(1-phenylethyl)amine.

15. Pharmaceutical composition having the properties of an inhibitor R, which contains an effective amount of the compounds of formula I according to any one of claims 1 to 14 or its pharmaceutically acceptable salt and one or more pharmaceutically acceptable excipients.

16. The use of the compounds of formula I according to any one of claims 1 to 14 or its pharmaceutically acceptable salts for the production of Lek is stannage tools for the treatment or prevention of diseases, indirect R.

17. The compound according to claim 5, in which R2represents one Deputy, selected from H, halogen, C1-6-alkyl, -ORb'and-NRb'Rb'.

18. The compound according to claim 5, in which G represents C and R2represents N.

19. Connection p, in which R3represents phenyl, which optionally may be substituted by one or more halogen atoms.

20. The compound according to claim 5, in which G represents N, R2is an-otherband is located in position 2 of the pyrimidine cycle and Rbrepresents a C1-6-alkyl, substituted by one Deputy, selected from su and-ORh'.

21. Connection by claim 20, in which R3represents N.



 

Same patents:

FIELD: chemistry.

SUBSTANCE: described is a bromohydrate of 4-methoxy-7,7-dimethyl-9-(5'-carboxyamyl)amino-6H-7,8-dihydropyrimido-(4,5-b)-1,4-benzthiazine (hereinafter methiazine) and a method for synthesis of the said compound. Methiazine has anti-tumour and anti-reductase activity, which has cytostatic and cytotoxic effect which inhibits synthesis of nucleic acids and can be used in medicine. Bromohydrate of 4-methoxy-7,7-dimethyl-9-(5'-carboxyamyl)amino-6H-7,8-dihydropyrimido-(4,5-b)-1,4-benzthiazine of formula I , is obtained by reacting dimedone with ω-amino caproic acid in a medium of boiling isopropanol to obtain enamine-ketone which is subjected to bromation with bromosuccinimide with further treatment with 4-methoxy-5-amino-6-mercaptopyrimidine in a medium of boiling isopropanol.

EFFECT: improved method.

2 cl, 3 ex

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of formula (1) and their pharmaceutically acceptable salts as chemokine receptor CCR3 activity modulators, a pharmaceutical composition based on the said compounds, to synthesis method and use thereof. Said compounds can be used for treating and preventing diseases mediated by chemokine receptor CCR3 activity, such as inflammatory and allergic diseases etc. In general formula , R1 represents phenyl, [1,2,4]triazolo[4,3-a]pyridinyl, thiazolo [5,4-b]pyridinyl, benzothiazolyl, benzoxazolyl, pyridinyl, where each of the said phenyl or heterocycles can be substituted with one, two or three radicals R2; R2 each independently represents (C1-C6)halogenalkyl, halogen, COOR3; CONR3R4; R3 represents H or (C1-C6)alkyl; R4 represents H or (C1-C6)alkyl, R5 represents (C1-C6)alkyl, (C1-C6)alkoxy, (C3-C6)cycloalkyl; R6 each independently represents (C1-C6)alkoxy, (C1-C6)halogenalkyl, halogen, OR3, CN, CONR3R4; A represents C(CH3)2-CH2-CH2-, CH2-CH2-CH2- or B represents phenyl; D-E represents CH-CH2- or C=CH-, X-W-V represents N-C=CR7 or C=C-NR7; R7 represents H or (C1-C6)alkyl; Y represents NR4, O, S(O)n; i, j, m each equals 1, n equals 0 or 2.

EFFECT: increased effectiveness of using said compounds.

13 cl, 37 ex

FIELD: medicine.

SUBSTANCE: invention is related to derivatives of isothiourea of formula I, including their pharmaceutically acceptable salts, which possess properties of antagonist CXCR4. In compounds of formula I , where R1 means remainder of formula (a) , (b) or (c) , R2 means -(CR22R23)1-3-, R3 and R8 each means S, R4 and R5 each independently means C3-C12cycloalkyl, C1-C12alkyl or saturated C8-C12 polycyclic hydrocarbon remainder, such as adamantine, non-substituted phenyl or non-substituted benzyl unnecessarily substituted with group R25, R6 means H or C1-C6alkyl, R7 means CH, R9 means direct connection or -(CR22R23)1-2-, R10-R15 each means H, R16-R23 each independently means H, C1-C6alkyl, or R20 and R21 together with carbon atoms, to which they are connected, create a benzene ring, and R25 has one of values given above for R16-R23.

EFFECT: improved method for production of derivatives of isothiourea.

5 cl, 1 tbl, 24 ex

FIELD: chemistry.

SUBSTANCE: present invention relates to compounds of formula (I) and their pharmaceutically acceptable salts. The disclosed compounds have inhibitory effect on HsEg5. In formula (I) A is C=O or CH2; B is optionally substituted C1-6alkyl, D is O or N, where O is substituted with one R8, and where N is substituted with one or more R8, R1 and R2 together with the carbon atoms with which they are bonded form optionally substituted isothiazole or isoxazole, condensed with a pyrimidine ring, optionally substituted with a substitute which is C1-6 alkyl. Values of the rest of the radicals are given in the formula of invention.

EFFECT: invention relates to use of disclosed compounds in making medicinal agents with inhibitory effect on HsEg5, to a method of obtaining inhibitory effect on HsEg5, to a pharmaceutical composition which contains the disclosed compound as an active ingredient.

22 cl, 31 ex

FIELD: chemistry.

SUBSTANCE: invention relates to substituted N-acyl-2-aminothiazoles of formula (I) and their pharmaceutically acceptable salts as antagonist of adenosine receptor A2B and to a pharmaceutical composition based on the said compounds. In formula (I) X is -CH2-, -CH2CH2-, -(CH2)3- and O(CH2)-; R is a 5- or 6-member saturated or unsaturated carbocyclic or heterocyclic ring system, which can optionally contain one or more heteroatoms, chosen from N, O and S, where the said ring system is optionally substituted with one or more substitutes, chosen from a group consisting of halogen, hydroxy, lower alkyl, nitrile group, sulfonamide, aminosulfonyl, lower alkoxycarbonyl, lower alkylsufonyl, benzyl, benzoyl, phenylsulfonyl, and the said benzyl, benzoyl or phenylsulfonyl are optionally substituted with a halogen, trihalogeno-lower alkyl group; R1 is chosen from a group consisting of hydrogen, halogen or lower alkoxy group.

EFFECT: obtaining compounds which can be used for treating and preventing diseases caused by adenosine receptors A2B, such as diabetes, diabetic retinopathy, asthma and diarrhea.

FIELD: chemistry.

SUBSTANCE: claimed invention relates to novel derivatives of 2,6-dihydro-7H- pyrazolo[3,4-d]pyradazin-7-one, 1,4-dihydropyrazolo[3,4-b]thiazin-5(6H)-one; N-acylated 4-imidazo[1,2-a]pyridin-2-yl- and 4-imidazo[1,2-a]pyrimidin-2-yl- anilines; amides of [(4H-thieno[3,2-b]pyrrol-5-yl)carbonyl]pyperidin-4-carboxylic acid; amides of 2-(4-carbamoylpyperidin-1-yl)isonicotinic acid; amides of N-sulfonyl-1,2,3,4-tetrahydrochinolin-6-carboxylic acid; as well as to N-acylated 3-azolyl derivatives of 2-amino-4,5,6,7-tetrahydtithieno[2,3-c]pyridine possessing properties of Hh-signal cascade inhibitors.

EFFECT: compounds can be applied for use in pharmaceutical compositions and medications for treating diseases induced by abberant activity of Hedgehog (Hh) signal system, in particular, oncological diseases, for instance, for pancreatic carcinoma treatment.

23 cl, 13 dwg, 11 tbl, 26 ex

FIELD: chemistry.

SUBSTANCE: present invention relates to new annelated azaheterocyclic amides, including a pyrimidine fragment, with the general formula 1, method of obtaining them and their application in the form of free bases or their pharmaceutically accepted salts as inhibitors of P13K kinase, in compounds with the general formula 1: , where: X represents an oxygen atom, sulphur atom or not necessarily substituted at the nitrogen NH group, where the substitute is selected from lower alkyls and possibly a substituted aryl; Y represents an atom of nitrogen or substituted at the carbon atom CH group, where the substitute is selected from lower alkyls; Z represents an oxygen atom; R1 represents a hydrogen atom or not necessarily substituted C1-C6alkyl, or Z represents a nitrogen atom, which is together with a carbon atom, with which it is joined, form through Z and R1 annelated imidazole cycle; R2 and R3 independently from each other represent hydrogen, not necessarily substituted with C1-C6alkyl, C3-C6cycloalkyl, not necessarily substituted with phenyl, not necessarily substituted with 6-member aza-heteroaryl, under the condition, when Y represents a nitrogen atom, or R2 and R3 independently from each other represent not necessarily substituted C1-C6alkyl, not necessarily substituted with phenyl, not necessarily substituted with 5-7-member heterocycle with 1-2 heteroatoms, selected from nitrogen and oxygen, and possibly annelated with a phenyl ring, under the condition, when Y does not necessarily represent a substituted carbon atom at the CH group, and X represents an oxygen atom, sulphur atom, or R2 represents hydrogen, and R3 represents a substituted aminoC1-C6alkyl and not necessarily substituted 5-6-member aza-heterocycloalkyl, under the condition, when Y represents a group which is substituted at the CH atom, and X represents an oxygen atom, sulphur atom, or R2 represents hydrogen, and R3 represents phenyl which is not necessarily substituted, pyridyl which is not necessarily substituted, pyrimidinyl which is not necessarily substituted, under the conditions, when R1 represents a substituted aminoC1-C6alkyl, substituted C2-C3hydroxyalkyl and aza-heterocycloalkyl not necessarily substituted, Y represents a group with CH substituted, and X represents an oxygen atom, sulphur, and the substitute of the above indicated substituted alkyl, phenyl, heterocycle, pyridyl, pyrimidyl are selected from groups of hydroxyl-, cyano-groups, hydrogen, lower alkyls, possibly mono- or di-substituted lower alkyl sulfamoyl, carbamoyl, C1-C6alkoxycarbonyl, amino, mono- or di-lower alkyl-amine, N-(lower alkyl), N-(phenylC1-C6alkyl)amine, phenyl, possibly substituted with a halogen atom, C1-C6alkyl, haloid-C1-C6alkyl; phenylC1-C6alkyl, saturated or non-saturated 5-6-member heterocycle containing 1-2-heteroatoms, selected from nitrogen, oxygen and sulphur, and possible condensation with a benzene ring R4 represents hydrogen or a lower alkyl.

EFFECT: obtaining new annelated aza-heterocyclic amides, including a pyrimidine fragment, with the general formula with the possibility of their application in the form of free bases or their pharmaceutically accepted salts as inhibitors of PI3K kinase.

16 cl, 5 tbl, 5 ex

FIELD: chemistry; pharmacology.

SUBSTANCE: present invention relates to mono-sodium salt 5-[[(2,3-difluorophenyl)methyl]thio]-7-[[2-hydroxy-1-(hydroxymethyl)-1-methylethyl]amino]thiazole[4,5-d]pyrimidine-2(3H)-on as a modulator of the activeness of chemokine receptors, method of obtaining it and pharmaceutical composition on its basis, and also its application in production of medicinal agents.

EFFECT: obtaining compounds, which can find application in treatment of diseases mediated by chemokine receptors, such as asthma, allergic rhinitis, COPD (chronic obstructive pulmonary disease), inflammatory bowel disease, osteoarthritis, and rheumatoid arthritis.

10 cl, 2 ex

FIELD: chemistry; pharmacology.

SUBSTANCE: present invention relates to new condensed dicyclic nitrogen-containing heterocycles with the general formula (I), their pharmaceutically accepted salts and stereoisomers, possessing DGAT inhibiting action. In the compound of formula (I): , X is selected from a group, which consists of C(R1) and N; Y is selected from a group, which consists of C(R1), C(R2)(R2), N and N(R2); Z is selected from a group, which consists of O; W1 is selected from cyclo(C3-C6)alkyl, aryl and 5- or 6-member heteroaryl, containing 1-2 heteroatoms, selected from a group, which comprises of nitrogen and sulphur, W2 selected from cyclo(C3-C8)alkyl, (C5-C6)heterocycloalkyl, containing 1 or 2 heteroatoms, selected from groups, consisting of nitrogen or oxygen, benzol and 5-or 6-member heteroaryl, containing 1-2 nitrogen atoms as heteroatoms, L1 is the link; L2 is selected from a group consisting of links, 0, (C1-C4)alkylene and (C1-C4)oxyalkylene; m denotes 0 or 1; its not a must that when m denotes 1 and L2 denotes a link, the substitute for W2 can be integrated with the substitute for W1 forming a 5-or 6-member ring, condensed with c W1 forming a spiro-system or condensed with W2, where specified ring could be saturated or unsaturated and has 0 or 1 atom O, as a member of the ring R1 is H; R2 is H; R3 and R4 are independently selected from groups consisting of H and (C1-C8) alkyl; optionally, R3 and R4 can together form 3-, 4-, 5- or 6-member spirorings, R5 and R6 are independently H; optionally, when Y includes the group R1 or R2, R5 or R6 can be joined with R1 and R2 forming a 5- or 6-member condensate ring, containing a nitrogen atom, to which R5 or R6 are joined, and optionally containing an oxo-group; R7 is selected from a group, composed of H, (C1-C8) alkyl, halogen(C1-C4)alkyl, 0Ra and NRaRb ; Ra selected from groups composed of H and (C1-C8)alkyl; and Rb selected from groups consisting of H and (C1-C8)alkyl; a dotted line indicates a possible bond. The invention also relates to pharmaceutical compositions and applications of the compounds.

EFFECT: obtaining compounds which can be used for getting medicinal agents to treat or prevent diseases or a mediated action state of DGAT, such as obesity, diabetes, syndrome X, resistance of insulin, hyperglycemia, hyperinsulinemia, hypercholesterolemia, hyperlipidemia, hypertriglyceridemia, disease of non-alcoholic fatty infiltration of the liver, atherosclerosis, arteriosclerosis, coronary artery disease and myocardial infarction.

33 cl, 17 dwg, 11 tbl, 391 ex

FIELD: chemistry.

SUBSTANCE: in general formula (I) , R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R11 and R12 can be similar or different and represent, each independently, hydrogen, halogen, hydroxyl, unsubstituted (C1-C6)alkyl, (C1-C6)alkoxy, or neighbouring groups R2 and R3 together with carbon atoms to which they are bound, can form benzol ring; R13 and R14 can be similar or different and represent each independently, hydrogen, unsubstituted (C1-C6)alkyl, optionally, R13 and R14 together with nitrogen atom can form 5-, 6-member heterocyclic ring, where heterocycle also can be substituted (C1-C6)alkyl, and it can have "additional heteroatoms", selected from O, N; "n" is an integer in interval from 1 to 4, and carbon chain, to which it relates is linear.

EFFECT: compound possess the characteristic of activity modulators 5-HT and can be applied for treatment of such diseases as anxiety, depression, convulsive syndromes, migraine.

15 cl, 67 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: described are derivatives of 5H-pyrazolo[1,5-c][1,3]benzoxasin-5-yl)phenylmethanon of formula , possessing ability to inhibit HIV replication, where values of R1, R2, R3 substitutes are given in invention formula. Also describes is pharmaceutical preparation and application of compound for obtaining medication applied for treatment of conditions associated with HIV infection.

EFFECT: claimed compounds are applicable for prevention or treatment of HIV-produced infection and for AIDS treatment.

15 cl, 3 tbl, 5 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel compounds of formula I with anti-HIV activity , where R1 represents C1-6(Ar1)alkyl or C1-6(Ar1)oxyalkyl; R2 represents hydrogen or OR14; R3 represents hydrogen, halogen, hydroxyl, cyano, C1-6alkyl, C5-7cycloalkenyl, C1-6halogenalkyl, C1-6alkoxy, C1-6alkylthio, N(R8)(R9), NHAr2, N(R6)COR7, OCON(R8)(R9), OCH2CON(R9)(R9), CO2R6, CON(R8)(R9), SOR7, S(=N)R7, SO2R7, SO2N(R6)(R6), PO(OR6)2, C2-4(R12)alkynyl, R13, Ar2 or Ar3; R4 represents hydrogen, halogen, C1-6alkyl or C1-6alkoxy; R5 represents hydrogen, halogen, C1-6alkyl or C1-6alkoxy; R6 represents hydrogen or C1-6alkyl; R7 represents C1-7alkyl; R8 represents hydrogen or C1-6alkyl; R9 represents hydrogen, C1-6alkyl, C1-6hydroxyalkyl or C1-6(C1-6dialkylamino)alkyl; or N(R8)(R9) taken together represent azetidinyl, pyrrolydinyl, (R10)-piperidinyl, N-(R11)-piperazinyl, morpholinyl or dioxothiazinyl; R10 represents hydrogen; R11 represents hydrogen, C1-6alkyl, COR6 or CO2R6 ; R12 represents hydrogen, hydroxyl, N(R6)(R6), OSO2R7 or dioxothiazinyl; R13 represents dioxothiazinyl; R4 represents hydrogen or C1-6alkyl; Ar1 represents ,,,,,,,,; or Ar2 represents tetrazolyl, triazolyl, thiadiazolyl, pyrazolyl, imidazolyl, oxazolyl, thiazolyl, isoxazolyl, furanyl, thienyl, pyrrolyl, pyrimidinyl, pyrazinyl, pyridinyl, quinolinyl or indolyl, and is substituted with 0-2 substitutes selected from a group consisting of halogen, benzyl, C1-6alkyl, C1-6alkoxy, N((R8)(R9), CON(R8)(R9) and CO2R8; Ar3 represents phenyl substituted with 0-2 substitutes selected from a group consisting of halogen, cyano, hydroxy, C1-6alkyl, C1-6alkoxy, (C1-6alkoxy)methyl, C1-6halogenalkoxy, N(R8)(R9), CON(R6)(R6) and CH2N(R8)(R9), or represents dioxolanylphenyl; and X-Y-Z represents C(R14)2OC(R14)2C(R14)2, C(R14)2OC(R14)2C(R14)2C(R14)2; or pharmaceutically acceptable salt thereof. The invention also relates to a pharmaceutical composition.

EFFECT: bicyclic heterocycles are disclosed, as well as their use HIV integrase inhibitors.

21 cl, 38 dwg, 8 tbl, 282 ex

FIELD: chemistry.

SUBSTANCE: present invention relates to a morpholine type cinnamide derivative with general formula I or its pharmacologically acceptable salt, where (a) R1, R2 , R3 and R4 are identical or different and each represents a hydrogen atom or C1-6alkyl group; X1 represents a C1-6alkylene group, where the C1-6alkylene group can be substituted with 1-3 hydroxyl groups or C1-6alkyl groups, or a C3-8cycloalkyl group formed by two C1-6alkyl groups all bonded to the same carbon atom of the C1-6alkylene group; Xa represents a methoxy group or a fluorine atom; Xb represents an oxygen atom or a methylene group, under the condition that Xb represents only an oxygen atom when Xa represents a methoxy group; and Ar1 is an aryl group, pyridinyl group which can be substituted with 1-3 substitutes selected from A1 group of substitutes; (b) Ar1-X1- represents a C5-7cycloalkyl group condensed with a benzene ring, where one methylene group in the C5-7cycloalkyl group can be substituted with an oxygen atom, the C5-7cycloalkyl group can be substituted with 1-3 hydroxyl groups and/or C1-6alkyl groups, and R1, R2, R3, R4, Xa and Xb assume values given in (a); (d) Ar1-X1- and R4 together with the nitrogen atom bonded to the Ar1-X1- group and the carbon atom bonded to the R4 group form a 5-7-member nitrogen-containing heterocyclic group which is substituted with an aryl group or a pyridinyl group, where one methylene group in the 5-7-member nitrogen-containing heterocyclic group can be substituted with an oxygen atom, and the aryl or pyridinyl group can be substituted with 1-3 substitutes selected from A1 group of substitutes, Xb is an oxygen atom, and R1, R2, R3 and Xa assume values given in (a) and (b); group A1 of substitutes: (1) halogen atom. The invention also relates to a pharmaceutical composition containing a formula I compound, which is useful in treating Alzheimer's disease, senile dementia, Down syndrome or amyloidosis.

EFFECT: obtaining novel morpholine type cinnamide derivatives with inhibitory effect on amyloid-β production.

17 cl, 9 tbl, 113 ex

FIELD: chemistry.

SUBSTANCE: invention relates to benzopyran derivatives of formula or

or their pharmaceutically acceptable salts, where R1 and R2 independently represent a hydrogen atom or a C1-6alkyl group, R3 is a hydroxyl group, R4 is a hydrogen atom, m is an integer ranging from 1 to 4, n is an integer ranging from 0 to 4, V is a single bond, CR7R8 or NR9, R5 is a hydrogen atom, R6 is a hydrogen atom, C1-6alkyl group, C3-8cycloalkyl group, C3-8cycloalkenyl group, amino group, C1-6alkylamino group, C6-14aryl group, C2-9heteroaryl group or C2-9heterocyclic group, A is a 5- or 6-member ring condensed with a benzene ring, and the ring can contain an oxygen atom, a nitrogen atom or a sulphur atom numbering from 1 to 3 or separately, or combined, the number of unsaturated bonds in the ring equals 1, 2 or 3, including the unsaturated bond in the condensed benzene ring, carbon atoms in the ring can represent carbonyl or thiocarbonyl.

EFFECT: compounds can be used as antiarrhythmic agents.

47 cl, 1 tbl, 98 ex

FIELD: chemistry.

SUBSTANCE: present invention relates to compounds of formula (I) and their pharmaceutically acceptable salts. The disclosed compounds have inhibitory effect on HsEg5. In formula (I) A is C=O or CH2; B is optionally substituted C1-6alkyl, D is O or N, where O is substituted with one R8, and where N is substituted with one or more R8, R1 and R2 together with the carbon atoms with which they are bonded form optionally substituted isothiazole or isoxazole, condensed with a pyrimidine ring, optionally substituted with a substitute which is C1-6 alkyl. Values of the rest of the radicals are given in the formula of invention.

EFFECT: invention relates to use of disclosed compounds in making medicinal agents with inhibitory effect on HsEg5, to a method of obtaining inhibitory effect on HsEg5, to a pharmaceutical composition which contains the disclosed compound as an active ingredient.

22 cl, 31 ex

FIELD: chemistry.

SUBSTANCE: invention relates to derivatives of 2,3-dihydro-6-nitroimidazo[2,1-b]oxazol of general formula (1), as well as to their optically active forms and pharmacologically acceptable salts: where values of R1, R2 and n are given in i.1 of invention formula.

EFFECT: development of compounds, which have bactericidal action against Mycobacterium tuberculosis, polyresistant Mycobacterium tuberculosis and can be applied as antituberculosis medication.

3 cl, 16 ex, 183 tbl, 1515 ex

FIELD: chemistry.

SUBSTANCE: claimed invention relates to novel derivatives of 2,6-dihydro-7H- pyrazolo[3,4-d]pyradazin-7-one, 1,4-dihydropyrazolo[3,4-b]thiazin-5(6H)-one; N-acylated 4-imidazo[1,2-a]pyridin-2-yl- and 4-imidazo[1,2-a]pyrimidin-2-yl- anilines; amides of [(4H-thieno[3,2-b]pyrrol-5-yl)carbonyl]pyperidin-4-carboxylic acid; amides of 2-(4-carbamoylpyperidin-1-yl)isonicotinic acid; amides of N-sulfonyl-1,2,3,4-tetrahydrochinolin-6-carboxylic acid; as well as to N-acylated 3-azolyl derivatives of 2-amino-4,5,6,7-tetrahydtithieno[2,3-c]pyridine possessing properties of Hh-signal cascade inhibitors.

EFFECT: compounds can be applied for use in pharmaceutical compositions and medications for treating diseases induced by abberant activity of Hedgehog (Hh) signal system, in particular, oncological diseases, for instance, for pancreatic carcinoma treatment.

23 cl, 13 dwg, 11 tbl, 26 ex

FIELD: chemistry.

SUBSTANCE: invention is related to the compound of general formula 1 or its tautomer or pharmaceutically acceptable salt, where W selected from N and CR4; X is selected from CH(R8), O, S, N(R8), C(=O), C(=O)O, C(=O)N(R8), OC(=O), N(R8)C(=O), C(R8)-CH and C(=R8); G1 - bicyclic or tricyclic condensed derivative of azepin, selected from general formulas 2-9 , or derivative of aniline of common formula 10 , where A1, A4, A7 and A10 are independently selected from CH2, C=O, O and NR10; A2, A3, A9, A11, A13, A14, A15, A19 and A20 are independently selected from CH and N; or A5 stands for covalent connection, and A6 represents S; or A5 stands for N=CH, and A6 represents covalent connection; A8 , A12 , A18 and A21 are independently selected from CH=CH, NH, NCH3 and S; A16 and A17 both represent CH2, or one from A16 and A17 represents CH2, and the one another is selected from C=O, CH(OH), CF2, O, SOc and NR10; Y is selected from CH=CH or S; R1 and R2 are independently selected from H, F, Cl, Br, alkyl, CF3 and group O-alkyl; R3 is selected from H and alkyl; R4-R7 are independently selected from H, F, Cl, Br, alkyl, CF3, OH and group O-alkyl; R8 is selected from H, (CH2)bR9 and (C=O)(CH2)bR9; R9 is selected from H, alkyl, possibly substituted aryl, possibly substituted heteroaryl, OH, groups O-alkyl, OC(=O)alkyl, NH2, NHalkyl, N(alkyl)2, CHO, CO2H, CO2alkyl, CONH2, CONHalkyl, CON(alkyl)2 and CN; R10 is selected from H, alkyl, group COalkyl and (CH2)dOH; R11 is selected from alkyl, (CH2)dAr, (CH2)dOH, (CH2)dNH2, group (CH2)aCOOalkyl, (CH2)dCOOH and (CH2)dOAr; R12 and R13 are independently selected from H, alkyl, F, CI, Br, CH(OCH3)2, CHF2, CF3, groups COOalkyl, CONHalkyl, (CH2)dNHCH2Ar, CON(alkyl)2, CHO, COOH, (CH2)dOH, (CH2)dNH2, N(alkyl)2, CONH(CH2)dAr and Ar; Ar is selected from possibly substituted heterocycles or possibly substituted phenyl; a is selected from 1, 2 and 3; b is selected from 1, 2, 3 and 4; c is selected from 0, 1 and 2; and d is selected from 0, 1, 2 and 3. Besides, the invention is related to pharmaceutical compound and to method for activation of vasopressin receptors of type 2.

EFFECT: compounds according to invention represent agonists of receptor of vasopressin V2, which stipulates for their application (another object of invention) for preparation of medicine for treatment of condition selected from polyuria, including polyuria, which is due to central diabetes insipidus, nocturnal enuresis of nocturnal polyurea, for control of enuresis, to postpone bladder emptying and for treatment of disorders related to bleeds.

21 cl, 228 ex

FIELD: medicine.

SUBSTANCE: invention offers analogues of quinazoline of the formula I

where A is bound at least with one of atoms of carbon in position 6 or 7 of the dicyclic ring; X represents N. A represents the group Q or Z including tautomeric group Z form where Q and Z, have the formulas resulted more low in which symbols and radicals, have the value specified in item 1 of the formula of the invention. R1 represents phenyl, substituted -(G)nOAr or -O(G)nAr and where phenyl is unessentially replaced by halogen or C1-C10alkyl; where G represents C1-C4alkylene, n is peer 0 or 1. And Ar represents phenyl either pyridyl or thiazolyl where Ar is unessentially substituted by 1-2 substituents chosen from halogen or C1-C10alkyl; R2 and R3 represent N. The bonds of the formula I are inhibitors of the receptor tyrosine kinases of type 1. The invention includes also a way of treatment of hyperproliferative diseases, such as a cancer, application of bonds of the formula 1 in manufacture of medical products and pharmaceutical composition on the basis of these bonds.

EFFECT: rising of efficiency of a composition and the method of treatment.

14 cl, 6 dwg, 63 ex

FIELD: chemistry.

SUBSTANCE: present invention relates to new annelated azaheterocyclic amides, including a pyrimidine fragment, with the general formula 1, method of obtaining them and their application in the form of free bases or their pharmaceutically accepted salts as inhibitors of P13K kinase, in compounds with the general formula 1: , where: X represents an oxygen atom, sulphur atom or not necessarily substituted at the nitrogen NH group, where the substitute is selected from lower alkyls and possibly a substituted aryl; Y represents an atom of nitrogen or substituted at the carbon atom CH group, where the substitute is selected from lower alkyls; Z represents an oxygen atom; R1 represents a hydrogen atom or not necessarily substituted C1-C6alkyl, or Z represents a nitrogen atom, which is together with a carbon atom, with which it is joined, form through Z and R1 annelated imidazole cycle; R2 and R3 independently from each other represent hydrogen, not necessarily substituted with C1-C6alkyl, C3-C6cycloalkyl, not necessarily substituted with phenyl, not necessarily substituted with 6-member aza-heteroaryl, under the condition, when Y represents a nitrogen atom, or R2 and R3 independently from each other represent not necessarily substituted C1-C6alkyl, not necessarily substituted with phenyl, not necessarily substituted with 5-7-member heterocycle with 1-2 heteroatoms, selected from nitrogen and oxygen, and possibly annelated with a phenyl ring, under the condition, when Y does not necessarily represent a substituted carbon atom at the CH group, and X represents an oxygen atom, sulphur atom, or R2 represents hydrogen, and R3 represents a substituted aminoC1-C6alkyl and not necessarily substituted 5-6-member aza-heterocycloalkyl, under the condition, when Y represents a group which is substituted at the CH atom, and X represents an oxygen atom, sulphur atom, or R2 represents hydrogen, and R3 represents phenyl which is not necessarily substituted, pyridyl which is not necessarily substituted, pyrimidinyl which is not necessarily substituted, under the conditions, when R1 represents a substituted aminoC1-C6alkyl, substituted C2-C3hydroxyalkyl and aza-heterocycloalkyl not necessarily substituted, Y represents a group with CH substituted, and X represents an oxygen atom, sulphur, and the substitute of the above indicated substituted alkyl, phenyl, heterocycle, pyridyl, pyrimidyl are selected from groups of hydroxyl-, cyano-groups, hydrogen, lower alkyls, possibly mono- or di-substituted lower alkyl sulfamoyl, carbamoyl, C1-C6alkoxycarbonyl, amino, mono- or di-lower alkyl-amine, N-(lower alkyl), N-(phenylC1-C6alkyl)amine, phenyl, possibly substituted with a halogen atom, C1-C6alkyl, haloid-C1-C6alkyl; phenylC1-C6alkyl, saturated or non-saturated 5-6-member heterocycle containing 1-2-heteroatoms, selected from nitrogen, oxygen and sulphur, and possible condensation with a benzene ring R4 represents hydrogen or a lower alkyl.

EFFECT: obtaining new annelated aza-heterocyclic amides, including a pyrimidine fragment, with the general formula with the possibility of their application in the form of free bases or their pharmaceutically accepted salts as inhibitors of PI3K kinase.

16 cl, 5 tbl, 5 ex

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of formula I , where R1 is C1-C7-alkyl; R2 is C1-C7-alkyl, C1-C7-haloalkyl, C3-C8-cycloalkyl; R3 is -NRaRb; possibly substituted phenyl, thiophenyl, furanyl, where the substitutes are selected from a group consisting of halogen, C1-C7-alkoxy, C1-C7-alkylsulphonyl and -C(O)O-C1-C7-alkyl; R4 is hydrogen or C1-C7-alkyl; R5 is hydrogen, halogen, C1-C7-alkyl, phenyl; or R5 together with R4 can form a ring selected from a group consisting of C5-C7-cycloalkyl, tetrahydrofuranyl, piperidine, tetrahydropyran, phenyl or pyridinyl, which can possibly be substituted with -C(O)O-C1-C7-alkyl; Ra and Rb together with the nitrogen atom to which they are bonded form piperidine; and to pharmaceutically acceptable salts thereof. The invention also relates to a medicinal agent based on the said compounds which has GABA-B receptor allosteric enhancement effect.

EFFECT: obtaining novel compounds and a medicinal agent based on the said compounds, which can be used in medicine for treating central nervous system disorders.

13 cl, 42 ex

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