New pyridine derivative and pyrimidine derivative (1)

FIELD: chemistry.

SUBSTANCE: invention relates to the new pyridine and new pyrimidine derivative, their pharmaceutically accepted salt or hydrate of the general formula (I): . The invention also relates to the pharmaceutical composition, which possesses the inhibiting activity with respect to the receptor of the growth factor of hepatocytes; to the inhibitor of the receptor of the growth factor of hepatocytes, the inhibitor of angiogenesis, the antitumor drug, the inhibitor of cancerous metastatic spreading, that contains the pharmacologically effective dose of the said compounds, its pharmaceutically acceptable salt or hydrate.

EFFECT: inhibitory activity.

27 cl, 45 tbl, 540 ex

 

The technical FIELD

The present invention relates to new pyridine derivative and a new pyrimidine derivative, their salts or hydrates, possessing inhibitory activity against the growth factor receptor of hepatocytes, antitumor activity, inhibitory activity against angiogenesis inhibitory activity against cancer metastasis, etc.

BACKGROUND of INVENTION

Described that overexpression of growth factor receptor of hepatocytes (hereinafter referred to as "HGFR") is observed in tumors of different types, such as pancreatic cancer, stomach cancer, cancer of the colon, rectum, breast cancer, prostate cancer, lung cancer, kidney cancer, a brain tumor or ovarian cancer (non-patent document 1). I believe that HGFR, expressed in these cancer cells, is involved in malignant cancer tissues (aberrant growth, invasion or growth of metastases), as HGFR causes autophosphorylation of the intracellular tyrosine kinase, which is constitutively or as a result of stimulation by the growth factor hepatocyte (hereinafter referred to as HGF).

Also described that HGFR is expressed in cells of the vascular endothelium and is involved in tumor angiogenesis, since HGF stimulates proliferation and migration of endothelial cells of blood vessels, Oper downnow HGFR (non-patent document 2).

It also describes that NK4, a peptide antagonist of HGF, blocks the signal HGF-HGFR, inhibiting the invasion of cancer cells and tumor angiogenesis (non-patent documents 3 and 4).

Therefore, I believe that the compounds having inhibitory activity against HGFR, can be used as antitumor agents, an inhibitor of angiogenesis or growth inhibitor of cancer metastasis.

Low molecular weight compounds with inhibitory activity against HGFR, disclosed in patent documents 1, 2 and 3. However, in patent document 1 disclosed indole derivatives, in patent document 2 disclosed quinoline derivatives and hintline derivatives, as in patent document 3 is disclosed imidazole derivatives; thus, the compounds disclosed in these documents clearly different in structure from pyridine derivatives and pyrimidine derivatives of the present invention.

In patent document 4 are disclosed derivatives of pyridine and pyrimidine, similar in structure to the compounds of the present invention. However, in patent document 4 is not revealed inhibitory activity described therein, compounds, and compounds of the present invention, with respect to HGFR.

[Patent document 1] WO 02/096361

[Patent document 2] WO 03/000660

[Patent document is t 3] WO 03/087026

[Patent document 4] WO 02/032872

[Non-patent document 1] Oncology Reports, 5, 1013-1024 (1998)

[Non-patent document 2] Advances in Cancer Research, 67, 257-279 (1995)

[Non-patent document 3] British Journal of Cancer, 84, 864-873 (2001)

[Non-patent document 4] Cancer Sci., 94, 321-327 (2003)

Description of the INVENTION

The object of the present invention is a compound having antitumor activity, inhibitory activity against angiogenesis or inhibitory activity against cancer metastasis, and this activity is due to inhibition abberant cell growth, morphological changes and hypermobility by modulating the activity of HGFR in vivo.

In the result of painstaking research on the above subject, the authors present invention successfully synthesized a new pyridine derivatives and pyrimidine derivatives represented by the formula (I), their salts or hydrates, and found that these compounds, their salts or hydrates have excellent inhibitory activity against HGFR, as well as antitumor activity, inhibitory activity against angiogenesis or inhibitory activity against cancer metastasis, which was the subject of the present invention.

Namely, the present invention provides the following.

[1] the Connection, the pre is submitted by the following formula, its salt or hydrate:

where R1represents C1-6alkyl, C2-6alkenyl, C2-6quinil, C3-10cycloalkyl, C6-10aryl, C1-6alkoxy, 5-10-membered heteroaryl, 3-10-membered nonaromatic heterocyclic group or a group represented by the formula-NR11aR11band R1may be substituted by the Deputy selected from foster group or A substitutional group B, where R11aand R11bmay be the same or different and each represents hydrogen, C1-6alkyl, C3-6alkenyl, C3-6quinil, C3-10cycloalkyl, C6-10aryl, C1-6alkoxy, 5-10-membered heteroaryl or 4-10-membered non-aromatic heterocyclic group, and R11aand R11bcan be substituted by the Deputy selected from foster group or A substitutional group B;

R2and R3represent hydrogen;

R4, R5, R6and R7may be the same or different and each denotes hydrogen, halogen, hydroxyl, cyano, trifluoromethyl, C1-6alkyl, C2-6alkenyl, C2-6quinil, C1-6alkoxy, amino, mono-C1-6alkylamino, di-C1-6alkylamino or a group represented by the formula-CO-R12where R12denotes hydrogen, hydroxyl, C1-6alkyl, C1-6alkoxy, amino, mono-C1-6Alki is amino or di-C 1-6alkylamino;

R8denotes hydrogen or C1-6alkyl;

R9represents C1-6alkyl, C2-6alkenyl, C2-6quinil, C3-10cycloalkyl, C6-10aryl, C3-10cycloalkyl-C1-6alkyl, C6-10aryl-C1-6alkyl, C1-6alkoxy, 5-10-membered heteroaryl, 3-10-membered nonaromatic heterocyclic group, a 5-10 membered heteroaryl-C1-6alkyl, 3-10-membered nonaromatic heterocyclic C1-6alkyl or a group represented by the formula-NR11aR11band R9may be substituted by the Deputy selected from foster group or A substitutional group B, where R11aand R11bhave the above meaning;

V1and V2may be the same or different and each represents oxygen or sulfur;

W represents a group represented by formula-N(RW3)-, where RW3denotes hydrogen or C1-6alkyl;

X denotes a group represented by formula-C(R10)=or nitrogen, where R10denotes hydrogen, halogen, cyano, C1-6alkyl, C2-6alkenyl, C2-6quinil or a group represented by the formula-CO-R12where R12has the above meaning; and

Y represents oxygen, sulfur, sulfinil, sulfonyl or a group represented by formula-N(RY)-, where RYdenotes hydrogen or C1-6alkyl,

the de replacement group A includes halogen, hydroxyl, mercapto, nitro, cyano and oxo;

where the replacement group B includes C1-6alkyl, C2-6alkenyl, C2-6quinil, C3-10cycloalkyl, C6-10aryl, 5-10-membered heteroaryl, 3-10-membered nonaromatic heterocyclic group, a C1-6alkoxy, C3-6alkenylacyl, C3-6alkyloxy, C3-10cycloalkane, C6-10aryloxy, 5-10-membered, heteroaromatic, 4-10-membered non-aromatic heterocyclic oxygraph, C1-6alkylthio, C3-6alkanity, C3-6alkylthio, C3-10cycloalkyl, C6-10aaltio, 5-10-membered, heteroaromatic, 4-10-membered non-aromatic heterocyclic tigroup and a group represented by the formula-T1-T2-T3and each group of replacement of group B may be substituted by the Deputy selected from foster group C, where T1denotes a direct bond or C1-6alkylen, T2denotes a carbonyl, sulfinil, sulfonyl, a group represented by formula-C(=O)-O-, a group represented by formula-O-C(=O)-, a group represented by the formula-SO2-O-, a group represented by formula-O-SO2-, a group represented by the formula-NRT1-, a group represented by formula-C(=O)-NRT1-, a group represented by the formula-NRT1-C(=O)-, a group represented by the formula-SO2-NRT1-or a group represented by formula the th-NR T1-SO2-T3denotes hydrogen, C1-6alkyl, C3-6alkenyl, C3-6quinil, C3-10cycloalkyl, C6-10aryl, 5-10-membered heteroaryl or 4-10-membered non-aromatic heterocyclic group, and RT1denotes hydrogen or C1-6alkyl; and

where the substitute group C includes halogen, hydroxyl, mercapto, nitro, cyano, oxo, C1-6alkyl, C2-6alkenyl, C2-6quinil, C3-10cycloalkyl, C6-10aryl, 5-10-membered heteroaryl, 3-10-membered nonaromatic heterocyclic group, a C1-6alkoxy and C1-6alkylthio.

[2] the Compound according to item [1], its salt or hydrate, where R1represents C1-6alkyl, optionally substituted Deputy selected from foster group or A substitutional group B described in paragraph [1].

[3] the Compound according to item [1], its salt or hydrate, where R1represents C1-6alkyl, optionally substituted Deputy selected from foster group D,

where the substituting group D includes amino, mono-C1-6alkylamino and di-C1-6alkylamino.

[4] the Compound according to item [1], its salt or hydrate, where R1indicates 3-10-membered nonaromatic heterocyclic group optionally substituted by a Deputy selected from foster group or A substitutional group B described in paragraph [1].

[5 Connection pun is that [1], its salt or hydrate, where R1refers to a group represented by the formula (II):

where a denotes an integer from 1 to 4

or a group represented by the formula (III):

where b is an integer from 1 to 3, and Z represents oxygen, sulfur, carbonyl, sulfonyl or a group represented by the formula-NRZ-where RZdenotes hydrogen or C1-6alkyl,

moreover, the group represented by formula (II) or (III)can be substituted by the Deputy selected from foster group or A substitutional group B described in paragraph [1].

[6] the Compound according to item [1], its salt or hydrate, where R1indicates azetidin-1-yl, pyrrolidin-1-yl, piperidine-1-yl, azepin-1-yl, piperazine-1-yl, diazepan-1-yl, morpholine-4-yl, thiomorpholine-4-yl or 1,1-diocletianopolis-4-yl, each of the above groups may be substituted by the Deputy selected from foster group E,

where the replacement group E includes halogen, hydroxyl, mercapto, cyano, formyl, oxo, C1-6alkyl, C3-10cycloalkyl, C1-6alkoxy, amino, mono-C1-6alkylamino, di-C1-6alkylamino, azetidine, pyrrolidine, piperidinyl, piperazinil, diazepan and a group represented by the formula-T4-T5where T4denotes a carbonyl or sulfonyl, and T5oboznachaet the C 1-6alkyl, C3-10cycloalkyl, azetidine, pyrrolidine, piperidinyl, hydroxyl, C1-6alkoxy, amino, mono-C1-6alkylamino or di-C1-6alkylamino,

where each group from foster group E may be substituted by hydroxyl, C1-6the alkyl, CI-C1-6alkylamino, azetidinol or pyrrolidinium.

[7] the Compound according to item [1], its salt or hydrate, where R1indicates azetidin-1-yl, pyrrolidin-1-yl, piperidine-1-yl, azepin-1-yl, piperazine-1-yl, diazepan-1-yl or morpholine-4-yl, each of the above groups may be substituted by the Deputy selected from foster group E',

where the replacement group E' includes methyl, ethyl, dimethylamino, azetidine, pyrrolidine, piperidinyl and piperazinil,

where each group from foster group E may be substituted by hydroxyl, stands, dimethylamino, azetidinol or pyrrolidinium.

[8] the Compound according to item [1], its salt or hydrate, where R1refers to a group represented by the formula-NR11aR11bwhere R11aand R11bhave the same meaning as in paragraph [1].

[9] the Compound according to item [1], its salt or hydrate, where R1refers to a group represented by the formula-NR11cR11dwhere R11cdenotes hydrogen or C1-6alkyl, and R11drepresents C1-6alkyl or a group represented by the formula (IV)

where c denotes an integer from 1 to 3, and Z1denotes oxygen, sulfur, carbonyl, sulfonyl or a group represented by the formula-NRZ1-where RZ1denotes hydrogen or C1-6alkyl, and R11dmay be substituted by the Deputy selected from foster group or A substitutional group B described in paragraph [1].

[10] the Compound according to item [1], its salt or hydrate, where R1refers to a group represented by the formula-NR11eR11fwhere R11edenotes hydrogen or C1-6alkyl, and R11frepresents C1-6alkyl, pyrrolidin-3-yl, piperidine-3-yl, piperidine-4-yl or tetrahydropyran-4-yl, and R11fmay be substituted by the Deputy selected from foster group E, specified in paragraph [6].

[11] the Compound according to item [1], its salt or hydrate, where R1refers to a group represented by the formula-NR11gR11hwhere R11gdenotes hydrogen or methyl, and R11hdenotes n-propyl, n-butyl, pyrrolidin-3-yl, piperidine-3-yl, piperidine-4-yl or tetrahydropyran-4-yl, and R11hmay be substituted by the Deputy selected from foster group E"

where the replacement group E" includes methyl, ethyl, n-propyl, acetyl, dimethylamino, diethylamino, azetidine, pyrrolidine and piperazinil,

where each group from foster group E can be replaced by stands or dimethylamino.

[12] the Compound according to any one of items [1]to[11], its salt or hydrate, where R4, R5, R6and R7may be the same or different, each represents hydrogen, halogen or C1-6alkyl.

[13] the Compound according to any one of items [1]to[12], its salt or hydrate, where R8denotes hydrogen.

[14] the Compound according to any one of items [1]to[13], its salt or hydrate, where V1denotes oxygen.

[15] the Compound according to any one of items [1]to[14], its salt or hydrate, where X denotes a group represented by formula-C(R10a)=, where R10adenotes hydrogen, halogen or cyano.

[16] the Compound according to any one of items [1]to[14], its salt or hydrate, where X denotes nitrogen.

[17] the Compound according to any one of paragraphs [1]-[16], its salt or hydrate, where Y denotes oxygen.

[18] the Compound according to any one of items [1]to[17], its salt or hydrate, where V2denotes sulfur.

[19] the Compound according to any one of items [1]to[17], its salt or hydrate, where W denotes a group represented by the formula-NH-and V2denotes sulfur.

[20] the Compound according to any one of items [1]to[17], its salt or hydrate, where V2denotes oxygen.

[21] the Compound according to any one of items [1]to[17], its salt or hydrate, where W denotes a group represented by the formula-NH-and V2denotes oxygen.

[22] the Compound according to any one of paragraphs [1]-[21], its salt or the guy who Rath, where R9represents C1-6alkyl, C3-10cycloalkyl, C3-10cycloalkyl-C1-6alkyl, C6-10aryl-C1-6alkyl, 5-10-membered heteroaryl-C1-6alkyl or 3-10-membered nonaromatic heterocyclic-C1-6alkyl, and R9may be substituted by the Deputy selected from foster group or A substitutional group B described in paragraph [1].

[23] the Compound according to any one of paragraphs [1]-[21], its salt or hydrate, where R9represents C3-10cycloalkyl-C1-6alkyl or C6-10aryl-C1-6alkyl, and R9may be substituted by the Deputy selected from foster group or A substitutional group B described in paragraph [1].

[24] a Pharmaceutical composition comprising the compound according to item [1], its salt or hydrate.

[25] the Inhibitor of growth factor receptor of hepatocytes containing compound according to item [1], its salt or hydrate.

[26] angiogenesis Inhibitor containing the compound according to item [1], its salt or hydrate.

[27] an Antitumor agent containing the compound according to item [1], its salt or hydrate.

[28] the Antitumor agent according to item [27], where the tumor is a pancreatic cancer, stomach cancer, cancer of the colon, rectum, breast cancer, prostate cancer, lung cancer, kidney cancer, brain cancer, or ovarian cancer.

[29] the Inhibitor of cancer metastasis, containing the third connection point [1], its salt or hydrate.

[30] a Method for prevention or treatment of disease, based on the inhibition of growth factor receptor of hepatocytes, which includes the introduction to the patient a pharmacologically effective dose of the compounds according to paragraph [1], its salt or hydrate.

[31] a Method for prevention or treatment of disease, based on the inhibition of angiogenesis, which involves injecting the patient a pharmacologically effective dose of the compounds according to paragraph [1], its salt or hydrate.

[32] a Method of preventing or treating tumors, which comprises the administration to a patient a pharmacologically effective dose of the compounds according to paragraph [1], its salt or hydrate.

[33] a Method of preventing or treating tumors by item [32], where the tumor is a pancreatic cancer, stomach cancer, cancer of the colon, rectum, breast cancer, prostate cancer, lung cancer, kidney cancer, brain cancer, or ovarian cancer.

[34] a Method of preventing or treating cancer metastasis, which involves injecting the patient a pharmacologically effective dose of the compounds according to paragraph [1], its salt or hydrate.

[35] Use of the compound according to item [1], its salt or hydrate, in industrial production of inhibitor of growth factor receptor of hepatocytes.

[36] the Use of compounds according to paragraph [1], its salt or hydrate, industrial flooring is the use of an inhibitor of angiogenesis.

[37] Use of the compound according to item [1], its salt or hydrate, industrial receiving antitumor agents.

[38] the Use of paragraph [37], where the tumor is a pancreatic cancer, stomach cancer, cancer of the colon, rectum, breast cancer, prostate cancer, lung cancer, kidney cancer, brain cancer, or ovarian cancer.

[39] the Use of compounds according to paragraph [1], its salt or hydrate, in industrial production of inhibitor of cancer metastasis.

Below is the definition used in this document symbols and terms, as well as a detailed description of the present invention.

Some structural formulas of the compounds described in the present description, for convenience, represent only one isomeric form, however, this invention encompasses all geometric isomers and optical isomers based on asymmetric carbons, stereoisomers and tautomers, and mixtures of these isomers that relate to these structures, not limited to, any formula, provided for convenience. Thus, the compounds of this invention include all of the optically active or racemic forms of the compounds containing asymmetric carbon atoms, for no particular limitations on this invention. If the compounds may exist in polymorphic Krista is symbolic forms, restrictions on these forms also exist, and the connection can be in one crystalline form or in a mixture of different crystalline forms, at the same time, the scope of the present invention is enabled anhydrate and hydrates of the compounds of this invention.

The so-called metabolite, which is a compound formed from the compounds of the present invention as a result of metabolism in vivo by oxidation, recovery, hydrolysis, conjugation and other processes, as well as the so-called prodrug, which is a compound that is transformed into the result of metabolism in vivo by oxidation, recovery, hydrolysis, conjugation and other processes, in the compound of the present invention, also included in the scope of formulas of the present invention.

The term "salt" includes a salt of an inorganic acid, salt with organic acid, salt with inorganic base, a salt with organic base, salts of acidic or basic amino acids, among which preferred is a pharmaceutically acceptable salt.

The preferred salt of the inorganic acid includes, for example, salts of hydrochloric acid, Hydrobromic acid, sulfuric acid, nitric acid and phosphoric acid. Preferred organic salt is coy acid includes, for example, salt of acetic acid, succinic acid, fumaric acid, maleic acid, tartaric acid, citric acid, lactic acid, stearic acid, benzoic acid, methanesulfonic acid, econsultancy acid and p-toluensulfonate acid.

The preferred salt of an inorganic base includes, for example, salt of an alkali metal such as sodium salt and potassium salt, alkaline earth metal, such as salt and calcium salt, magnesium salt, aluminum salt and ammonium. The preferred salt of the organic base includes, for example, salt diethylamine, diethanolamine, meglumine and N,N-dibenziletilendiaminom.

The preferred salt with acidic amino acids include, for example, salt of aspartic acid and glutamic acid. The preferred salt of the basic amino acid includes, for example, salt of arginine, lysine and ornithine.

The term "halogen" denotes fluorine, chlorine, bromine or iodine.

The term "C1-6alkyl" denotes alkyl straight or branched chain, containing from 1 to 6 carbon atoms and includes, as specific examples, methyl, ethyl, 1-propyl (n-propyl), 2-propyl (ISO-propyl), 2-methyl-1-propyl (ISO-butyl), 2-methyl-2-propyl (t-butyl), 1-butyl (n-butyl), 2-butyl (sec-butyl), 1-pentyl, 2-pentyl, 3-pentyl, 2-methyl-1-butyl, 3-methyl-1-butyl, 2-methyl--butyl, 3-methyl-2-butyl, 2,2-dimethyl-1-propyl, 1-hexyl, 2-hexyl, 3-hexyl, 2-methyl-1-pentyl, 3-methyl-1-pentyl, 4-methyl-1-pentyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl, 2-methyl-3-pentyl, 3-methyl-3-pentyl, 2,3-dimethyl-1-butyl, 3,3-dimethyl-1-butyl, 2,2-dimethyl-1-butyl, 2-ethyl-1-butyl, 3,3-dimethyl-2-butyl, 2,3-dimethyl-2-butyl.

The term "C2-6alkenyl" means an alkenyl straight or branched chain, containing one double bond and 2 to 6 carbon atoms, and includes, as specific examples, ethynyl (vinyl), 1-propenyl, 2-propenyl (allyl), 1-butenyl, 2-butenyl, 3-butenyl, pentenyl and hexenyl.

The term "C3-6alkenyl" means an alkenyl straight or branched chain, containing one double bond and from 3 to 6 carbon atoms, and includes, as specific examples, 2-propenyl (allyl), 2-butenyl, 3-butenyl, pentenyl and hexenyl.

The term "C2-6quinil" means quinil straight or branched chain, containing one triple bond and 2 to 6 carbon atoms, and includes, as specific examples, ethinyl, 1-PROPYNYL, 2-PROPYNYL, 1-butynyl, 2-butynyl, 3-butynyl, pentenyl and hexenyl.

The term "C3-6quinil" means quinil straight or branched chain, containing one triple bond and from 3 to 6 carbon atoms, and includes, as specific examples, 2-about inil, 2-butenyl, 3-butenyl, pentenyl and hexenyl.

The term "C1-6alkylene" denotes a divalent group resulting from the removal of any one of a hydrogen atom from C1-6of alkyl"defined above, and includes, as a specific example, methylene, 1,2-ethylene, 1,1-ethylene, 1,3-propylene, tetramethylene, pentamethylene and hexamethylene.

The term "C3-10cycloalkyl" denotes a mono - or di-tsiklicheskuyu saturated aliphatic hydrocarbon group containing from 3 to 10 carbon atoms, and includes, as specific examples, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cycloneii, cyclodecyl, bicyclo[2.1.0]pentyl, bicyclo[3.1.0]hexyl, bicyclo[2.1.1]hexyl, bicyclo[4.1.0]heptyl, bicyclo[2.2.1]heptyl (norbornyl), bicyclo[3.3.0]octyl, bicyclo[3.2.1]octyl, bicyclo[2.2.2]octyl, bicyclo[4.3.0]nonyl, bicyclo[3.3.1]nonyl, bicyclo[4.4.0]decyl (decalin) and bicyclo[3.3.2]decyl.

The term "C6-10aryl" refers to aromatic cyclic hydrocarbon group containing from 6 to 10 carbon atoms, and includes, as a specific example, phenyl, 1-naphthyl, 2-naphthyl, indenyl, azulene and heptenyl.

The term "heteroatom" means nitrogen, oxygen or sulfur.

The term "5-to 10-membered heteroaryl" refers to an aromatic cyclic group containing 5 to 10 atoms, the image of the common cycle, and from 1 to 5 heteroatoms, and includes, as specific examples, furyl, thienyl, pyrrolyl, imidazolyl, triazolyl, tetrazolyl, thiazolyl, pyrazolyl, oxazolyl, isoxazolyl, isothiazolin, furutani, thiadiazolyl, oxadiazolyl, pyridyl, pyrazinyl, pyridazinyl, pyrimidinyl, triazinyl, purinol, pteridinyl, hinely, ethanolic, naphthylidine, honokalani, cinnoline, hintline, phthalazines, imidazopyridine, imidazothiazoles, imidazolidinyl, benzothiazolyl, benzoxazolyl, benzimidazolyl, indolyl, isoindolyl, indazoles, pyrrolopyridine, cyanopyridyl, properity, benzothiadiazoles, benzoxadiazole pyridopyrimidines, benzofuran, sensational and cyanophoric.

Preferred examples of the "5-to 10-membered heteroaryl" include furyl, thienyl, pyrrolyl, imidazolyl, thiazolyl, pyrazolyl, oxazolyl, isoxazolyl, isothiazolin, pyridyl and pyrimidinyl.

The term "3-10-membered nonaromatic heterocyclic group" means

(1) a monocyclic or bicyclic non-aromatic heterocyclic group,

(2) containing from 3 to 10 atoms in the cycle,

(3) containing 1 to 2 heteroatoms among the atoms of the cycle,

(4) optionally containing 1 to 2 double bonds in the cycle,

(5) optionally containing 1 to 3 carbonyl, sulfinyl or sulfanilic groups in the loop.

If the group contains at the m of nitrogen in the cycle, the nitrogen can form a relationship, not involved in the formation of the loop. This group includes, as specific examples, aziridinyl, azetidin, pyrrolidinyl, piperidinyl, azepane, atacanli, piperazinil, diazepan, diisononyl, diazabicyclo[2.2.1]heptyl, morpholinyl, thiomorpholine, 1,1-dioxothiazolidine, oxiranyl, oxetanyl, tetrahydrofuryl, tetrahydropyranyl, dioxane, tetrahydrothieno, tetrahydrothiopyran, oxazolidinyl and diazolidinyl.

Preferred examples 3-10-membered nonaromatic heterocyclic group" include aziridinyl, azetidin, pyrrolidinyl, piperidinyl, azepane, piperazinil, diazepan, morpholinyl, thiomorpholine, 1,1-dioxothiazolidine, tetrahydrofuryl and tetrahydropyranyl.

The term "4-10-membered non-aromatic heterocyclic group" refers to

(1) a monocyclic or bicyclic non-aromatic heterocyclic group,

(2) containing from 4 to 10 atoms in the cycle,

(3) containing 1 to 2 heteroatoms among the atoms of the cycle,

(4) optionally containing 1 to 2 double bonds in the cycle,

(5) optionally containing 1 to 3 carbonyl, sulfinyl or sulfanilic groups in the loop.

If the group contains a nitrogen atom in the cycle, the nitrogen can form a relationship, not involved in the formation of the loop. This group includes, in whom the quality of concrete examples, azetidinol, pyrrolidinyl, piperidinyl, azepane, atacanli, piperazinil, diazepan, diisononyl, diazabicyclo[2.2.1]heptyl, morpholinyl, thiomorpholine, 1,1-dioxothiazolidine, oxetanyl, tetrahydrofuryl, tetrahydropyranyl, dioxane, tetrahydrothieno, tetrahydrothiopyran, oxazolidinyl and diazolidinyl.

Preferred examples 4-10-membered non-aromatic heterocyclic group" include azetidine, pyrrolidine, piperidinyl, azepane, piperazinil, diazepan, morpholinyl, thiomorpholine, 1,1-dioxothiazolidine, tetrahydrofuryl and tetrahydropyranyl.

The term "C3-10cycloalkyl-C1-6alkyl" refers to a group obtained by replacing one hydrogen atom of the above "C1-6alkyl" defined above, group "C3-10cycloalkyl", and includes, as specific examples, cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl, cycloheptylmethyl, cyclooctylmethyl, cyclononylmethyl, cyclobutylmethyl, bicyclo[2.2.1]heptamethyl (norbornylene), and bicyclo[4.4.0]decimeter (decoiler).

The term "C6-10aryl-C1-6alkyl" refers to a group obtained by replacing one hydrogen atom of the above "C1-6alkyl" defined above, group "C6-10aryl", and includes, as concrete is x examples benzyl, 1-naphthylmethyl, 2-naphthylmethyl, phenethyl, 1-naphtalate, and 2-naphtalate.

The term "5-to 10-membered heteroaryl-C1-6alkyl" refers to a group obtained by replacing one hydrogen atom of the above "C1-6alkyl" defined above, a group of 5-10-membered heteroaryl", and includes, as specific examples, furylmethyl, thienylmethyl, pyrrolidinyl, imidazolidinyl, triazolylmethyl, tetrazolyl, triazolylmethyl, parasailer, oxazolidinyl, isoxazolyl, isothiazolinones, pursenality, thiadiazolyl, oxadiazolyl, pyridylmethyl, personality, pyridinylmethyl, pyrimidinyl, triazolylmethyl, purolater, titilate, pyrrolidinyl, imidazolidinyl, triazolylmethyl, tetrazolate, triazolylmethyl, personility, oxazolidinyl, isoxazolyl, isothiazolines, pursenality, thiadiazolyl, oxadiazolyl, pyridylethyl, personality, pyridinylmethyl, pyrimidinyl and triazinyl.

Preferred examples of the "5-to 10-membered heteroaryl C1-6of alkyl" include furylmethyl, thienylmethyl, pyrrolidinyl, imidazolidinyl, triazolylmethyl, parasailer, oxazolidinyl, isoxazolyl, isothiazolinones, pyridylmethyl, pyrimidinyl, purolater, titilate, pyrrolidinyl, imidazolidinyl, triazolylmethyl, personility, oxazo iletin, isoxazolyl, isothiazolines, pyridylethyl and pyrimidinyl.

The term "3-10-membered nonaromatic heterocyclic-C1-6alkyl" refers to a group obtained by replacing one hydrogen atom of the above "C1-6alkyl" defined above, "a 3-10-membered heterocyclic group", and includes, as specific examples, aziridinyl, azetidinone, pyrrolidinyl, piperidinylmethyl, asianlineid, atenilol, piperazinylmethyl, diasability, diisocyanates, morpholinylmethyl, thiomorpholine, 1,1-dioxothiazolidine, oxiranylmethyl, acetanilides, tetrahydrofuranyl, tetrahydropyranyl, dioxadilol, tetrahydrocannibinol, tetrahydrothiopyrano, oxazolidinyl, diazolidinylurea, aziridination, azetidine, pyrrolidinyl, piperidinylmethyl, aseparate, asianlatin, piperazinylmethyl, diasability, diisocyanates, morpholinylmethyl, thiomorpholine, 1,1-dioxothiazolidine, oxiranylmethyl, acetanilides, tetrahydrofuranyl, tetrahydropyranyl, dioxalate, tetrahydrofolates, tetrahydrothiopyran, oxazolidinyl and thiazolidinediones.

Preferred examples 3-10-membered nonaromatic heterocyclic-C1-6of alkyl" include azetidinol pyrrolidinyloxyl, piperidinylmethyl, asianlineid, piperazinylmethyl, diasability, morpholinylmethyl, thiomorpholine, tetrahydrofuranyl, azetidine, pyrrolidinyl, piperidinylmethyl, aseparate, piperazinylmethyl, diasability, morpholinylmethyl, thiomorpholine and tetrahydrofuranyl.

The term "C1-6alkoxy" refers to a group obtained by adding oxygen to the end portion of the above group "C1-6alkyl", and includes, as specific examples, methoxy, ethoxy, 1-propoxy-(n-propoxy), 2-propoxy (ISO-propoxy), 2-methyl-1-propoxy (from-butoxy), 2-methyl-2-propoxy (tert-butoxy), 1 butoxy (n-butoxy), 2-butoxy (Deut-butoxy), 1-pentyloxy, 2-pentyloxy, 3-pentyloxy, 2-methyl-1-butoxy, 3-methyl-1-butoxy, 2-methyl-2-butoxy, 3-methyl-2-butoxy, 2,2-dimethyl-1-propoxy, 1-hexyloxy, 2-hexyloxy, 3 hexyloxy, 2-methyl-1-pentyloxy, 3-methyl-1-pentyloxy, 4-methyl-1-pentyloxy, 2-methyl-2-pentyloxy, 3-methyl-2-pentyloxy, 4-methyl-2-pentyloxy, 2-methyl-3-pentyloxy, 3-methyl-3-pentyloxy, 2,3-dimethyl-1-butoxy, 3,3-dimethyl-1-butoxy, 2,2-dimethyl-1-butoxy, 2-ethyl-1-butoxy, 3,3-dimethyl-2-butoxy and 2,3-dimethyl-2-butoxy.

The term "C1-6alkylthio" refers to a group obtained by adding sulfur to the end portion of the above group "C1-6alkyl", and includes, as a particular is reamers, methylthio, ethylthio, 1 property (n-propylthio), 2-propylthio (from-propylthio), 2-methyl-1-propylthio (from-butylthio), 2-methyl-2-propylthio (tert-butylthio), 1 butylthio (n-butylthio), 2-butylthio (Deut-butylthio), 1 pentylthio, 2-pentylthio, 3 pentylthio, 2-methyl-1-butylthio, 3-methyl-1-butylthio, 2-methyl-2-butylthio, 3-methyl-2-butylthio, 2,2-dimethyl-1-propylthio, 1-hexylthio, 2-hexylthio, 3-hexylthio, 2-methyl-1-pentylthio, 3-methyl-1-pentylthio, 4-methyl-1-pentylthio, 2-methyl-2-pentylthio, 3-methyl-2-pentylthio, 4-methyl-2-pentylthio, 2-methyl-3-pentylthio, 3-methyl-3-pentylthio, 2,3-dimethyl-1-butylthio, 3,3-dimethyl-1-butylthio, 2,2-dimethyl-1-butylthio, 2-ethyl-1-butylthio, 3,3-dimethyl-2-butylthio and 2,3-dimethyl-2-butylthio.

The term "C3-6alkenylacyl" refers to a group obtained by adding oxygen to the end portion of the above group "C3-6alkenyl", and includes, as specific examples, 2-propenyloxy (allyloxy), 2-butenyloxy, 3 butenyloxy, pentyloxy, hexenoate.

The term "C3-6alkanity" refers to a group obtained by adding sulfur to the end portion of the above group "C3-6alkenyl", and includes, as specific examples, 2-propylthio (allylthio), 2-butylthio, 3 butylthio, pentylthio, hexanite.

The term "C3-6alkyloxy" refers to a group obtained by adding sour is an ode to the end portion of the above group "C 3-6quinil", and includes, as specific examples, 2-propenyloxy, 2-butenyloxy, 3 butenyloxy, pentyloxy, hexyloxy.

The term "C3-6alkylthio" refers to a group obtained by adding sulfur to the end portion of the above group "C3-6quinil", and includes, as specific examples, 2-propylthio, 2-butylthio, 3 butylthio, pentylthio, hexylthio.

The term "C3-10cycloalkane" refers to a group obtained by adding oxygen to the end portion of the above group "C3-10cycloalkyl", and includes, as specific examples, cyclopropane, CYCLOBUTANE, cyclopentyloxy, cyclohexyloxy, cycloheptylamine, cyclooctylamine.

The term "C3-10cycloalkyl" refers to a group obtained by adding sulfur to the end portion of the above group "C3-10cycloalkyl", and includes, as specific examples, cyclopropylethyl, cyclobutyl, cyclopentyl, cyclohexylthio, cycloheptyl, cyclooctyl.

The term "C6-10aryloxy" refers to a group obtained by adding oxygen to the end portion of the above group "C6-10aryl", and includes, as specific examples, phenoxy, 1 naphthoxy, 2-naphthoxy, inderalici, Azulejos and is heptylaniline.

The term "C6-10aristeo" refers to a group obtained by adding sulfur to the end portion of the above group "C6-10aryl", and includes, as specific examples, phenylthio, 1 naphthylthio, 2-naphthylthio, indenity, asplenietea, catalanello.

The term "5-to 10-membered, heteroaromatic" refers to a group obtained by adding oxygen to the end portion of the above groups of 5-10-membered heteroaryl", and includes, as specific examples, forelocks, titilate, pyrrolidone, imidazolidine, triazoline, thiazolidone, pyrazolinone, oxazolidone, isoxazolidine, isothiazolinone, furazolidone, thiadiazolidine, oxadiazolidine, pyridyloxy, pyrazinone, pyridazinone, pyrimidinone, triazinone.

The term "5-to 10-membered, heteroaromatic" refers to a group obtained by adding sulfur to the end portion of the above groups of 5-10-membered heteroaryl", and includes, as specific examples, furylthio, tianity, Peralillo, imidazolidine, triazoline, thiazolino, personilty, oxazolyl, isoxazolyl, isothiazoline, horasanli, thiadiazolyl, oxadiazolyl, pyridylthio, personilty, pyridazinyl, pyrimidinyl, trainelli.

The term "4-10-membered nonaromatic heterocycles the th oxygraph" refers to a group, obtained by adding oxygen to the end portion of the above "4-10-membered non-aromatic heterocyclic group", and includes, as specific examples, azetidinone, pyrrolidinyloxy, piperidinyloxy, asianlogic, ashkanasy, piperidinyloxy, diazepamrx, diisocyanate, morpholinoethoxy, thiomorpholine, 1,1-dioxothiazolidine, oxyanions, tetrahydrofurane, tetrahydropyranyloxy, tetrahydropyranyloxy, tetrahydropyranyloxy.

The term "4-10-membered non-aromatic heterocyclic tighrope" refers to a group obtained by adding sulfur to the end portion of the above "4-10-membered non-aromatic heterocyclic group", and includes, as specific examples, azetidine, pyrrolidine, piperidinyl, aseanindia, atacanli, piperazinyl, diasability, diisocyanato, oxetanyl, tetrahydrofuryl, tetrahydropyranyl, tetrahydrothieno, tetrahydrothiopyrano.

The term "mono-C1-6alkylamino" refers to a group obtained by replacing one hydrogen atom of the amino group of the above "C1-6by alkyl", and includes, as specific examples, methylamino, ethylamino, 1 Propylamine (n-Propylamine), 2-Propylamine (from-Propylamine), 2-methyl-1-propyl) - Rev. Mino (from-butylamino), 2-methyl-2-propylamino (tert-butylamino), 1 butylamine (n-butylamino), 2-butylamine (Deut-butylamino), 1 pentylamine, 2-pentylamine, 3 pentylamine, 2-methyl-1-butylamine, 3-methyl-1-butylamino, 2-methyl-2-butylamine, 3-methyl-2-butylamino, 2,2-dimethyl-1-Propylamine, 1 hexylamino, 2-hexylamino, 3 hexylamino, 2-methyl-1-pentylamine, 3-methyl-1-pentylamine, 4-methyl-1-pentylamine, 2-methyl-2-pentylamine, 3-methyl-2-pentylamine, 4-methyl-2-pentylamine, 2-methyl-3-pentylamine, 3-methyl-3-pentylamine, 2,3-dimethyl-1-butylamino, 3,3-dimethyl-1-butylamino, 2,2-dimethyl-1-butylamino, 2-ethyl-1-butylamino, 3,3-dimethyl-2-butylamine and 2.3-dimethyl-2-butylamine.

The term "mono-C3-10cyclooctylamino" refers to a group obtained by replacing one hydrogen atom of the amino group of the above "C3-10cycloalkyl", and includes, as specific examples, cyclopropylamino, cyclobutylamine, cyclopentylamine, cyclohexylamine, cycloheptylamine, cyclooctylamine.

The term "mono-C6-10arylamino" refers to a group obtained by replacing one hydrogen atom of the amino group of the above "C6-10the aryl", and includes, as specific examples, phenylamino, 1 naphthylamine, 2-naphthylamine, Ingenierie, ashleymarie, heptylaniline.

The term "mono-5-10-membered, heteroarenes" refers to a group obtained in financial p is a result of the substitution of one hydrogen atom of the amino group of the aforementioned "5-to 10-membered heteroaryl", and includes, as specific examples, pyrilamine, thienylene, pyrrolidino, imidazolinone, triethylamine, tetrazolium, thiazolidine, pyrazolidine, oxazolidine, isoxazolidine, isothiazolinone, furazolidine, thiadiazolidine, oxadiazolidine, pyridylamino, pyrazinamide, pyridinylamino, pyrimidinamine, creatininemia.

Preferred examples of the "mono-5-10-membered heteroarylboronic include pyrilamine, thienylene, pyrrolidino, imidazolinone, thiazolidine, pyrazolidine, oxazolidine, isoxazolidine, isothiazolinone, pyridylamino, pyrimidinamine.

The term "mono-4-10-membered non-aromatic heterocyclic amino group" means a group resulting from substitution of one hydrogen atom of the amino group of the above "4-10-membered non-aromatic heterocyclic group", and includes, as specific examples, azetidinone, pyrrolidinium, piperidinium, aseanjapan, asianlamia, piperidylamine, diazepamonline, diisoquinoline, morpholinium, thiomorpholine, 1,1-dioxothiazolidine, acetanilide, tetrahydrofurfurylamine, tetrahydrofurfurylamine, tetrahydrocannabinol, tetrahydrothiopyrano.

Preferred examples of the "mono-4-10-membered non-aromatic GE is eroticlinks amino group" include pyrrolidinyl, piperidylamine, aseanjapan, piperidylamine, diazepamonline, morpholinium, thiomorpholine, tetrahydrofurfurylamine.

The term "CI-C1-6alkylamino" refers to a group obtained by substitution of two hydrogen atoms of the amino groups of the same or different groups of the above "C1-6of alkyl", and includes, as specific examples, N,N-dimethylamino, N,N-diethylamino, N,N-di-n-propylamino, N,N-di-ISO-propylamino, N,N-di-n-butylamino, N,N-di-ISO-butylamino, N,N-di-sec-butylamino, N,N-di-tert-butylamino, N-ethyl-N-methylamino, N-n-propyl-N-methylamino, N-ISO-propyl-N-methylamino, N-n-butyl-N-methylamino, N-ISO-butyl-N-methylamino, N-sec-butyl-N-methylamino and N-tert-butyl-N-methylamino.

Below are described all the substituents of the compounds of the present invention represented by the above formula (I).

The value of R1

R1represents C1-6alkyl, C2-6alkenyl, C2-6quinil, C3-10cycloalkyl, C6-10aryl, C1-6alkoxy, 5-10-membered heteroaryl, 3-10-membered nonaromatic heterocyclic group or a group represented by the formula-NR11aR11bwhere R11aand R11bmay be the same or different and each represents hydrogen, C1-6alkyl, C3-6alkenyl, C3-6quinil, C3-10cycloalkyl, C6-10aryl, C1-6alkoxy, 5-10-membered Goethe is aeril or 4-10-membered non-aromatic heterocyclic group, and R11aand R11bcan be substituted by the Deputy selected from foster group or A substitutional group B.

R1may be substituted by the Deputy selected from foster group or A substitutional group B.

Preferred examples of R1include C1-6alkyl, optionally substituted Deputy selected from foster group or A substitutional group B; 3-10-membered nonaromatic heterocyclic group optionally substituted by a Deputy selected from foster group or A substitutional group B; and a group represented by the formula-NR11aR11bwhere R11aand R11bhave the above significance, and R11aand R11bcan be substituted by the Deputy selected from foster group or A substitutional group B.

More preferred examples of R1include C1-6alkyl, optionally substituted Deputy selected from foster group D;

the group represented by formula (II):

where a denotes an integer from 1 to 4

or a group represented by the formula (III):

where b is an integer from 1 to 3, and Z represents oxygen, sulfur, carbonyl, sulfonyl or a group represented by the formula-NRZ-where RZdenotes hydrogen or C1-6alkyl and the group, represented by formula (II) or (III)can be substituted by the Deputy selected from foster group or A substitutional group B; or

the group represented by the formula-NR11cR11dwhere R11cdenotes hydrogen or C1-6alkyl, and R11drepresents C1-6alkyl or a group represented by the formula (IV):

where c denotes an integer from 1 to 3, and Z1denotes oxygen, sulfur, carbonyl, sulfonyl or a group represented by the formula-NRZ1-where RZ1denotes hydrogen or C1-6alkyl, and R11dmay be substituted by the Deputy selected from foster group or A substitutional group B.

Even more preferred examples of R1include C1-6alkyl, azetidin-1-yl, pyrrolidin-1-yl, piperidine-1-yl, azepin-1-yl, piperazine-1-yl, diazepan-1-yl, morpholine-4-yl, thiomorpholine-4-yl, 1,1-diocletianopolis-4-yl or a group represented by the formula-NR11eR11fwhere R11edenotes hydrogen or C1-6alkyl, R11frepresents C1-6alkyl, pyrrolidin-3-yl, piperidine-3-yl, piperidine-4-yl or tetrahydropyran-4-yl, and R11fmay be substituted by the Deputy selected from foster group E, and each of the above substituents can be substituted by the Deputy selected from foster group E.

Especially predpochtitelnei R 1include azetidin-1-yl, pyrrolidin-1-yl, piperidine-1-yl, piperazine-1-yl, diazepan-1-yl, morpholine-4-yl, each of the above substituents can be substituted by the Deputy selected from foster group E', or a group represented by the formula-NR11gR11hwhere R11gdenotes hydrogen or methyl, R11hdenotes n-propyl, n-butyl, pyrrolidin-3-yl, piperidine-3-yl, piperidine-4-yl or tetrahydropyran-4-yl, and R11hmay be substituted by the Deputy selected from foster group E".

The most preferred examples of R1include groups represented by the formulas:

The replacement value of the group A

Replacement group A includes halogen, hydroxyl, mercapto, nitro, cyano and oxo.

The replacement value of group B

Replacement group B includes C1-6alkyl, C2-6alkenyl, C2-6quinil, C3-10cycloalkyl, C6-10aryl, 5-10-membered heteroaryl, 3-10-membered nonaromatic heterocyclic group, a C1-6alkoxy, C3-6alkenylacyl, C3-6alkyloxy, C3-10cycloalkane, C6-10aryloxy, 5-10-membered, heteroaromatic, 4-10-membered non-aromatic heterocyclic oxygraph, C1-6alkylthio, C3-6alkanity, C3-6alkylthio, C3-10cycloalkyl, C6-10aaltio, 5-10 members of the tion of heteroaromatic, 4-10-membered non-aromatic heterocyclic tigroup and a group represented by the formula-T1-T2-T3where T1denotes a single bond or C1-6alkylen, T2denotes a carbonyl, sulfinil, sulfonyl, a group represented by formula-C(=O)-O-, a group represented by formula-O-C(=O)-, a group represented by the formula-SO2-O-, a group represented by formula-O-SO2-, a group represented by the formula-NRT1-, a group represented by formula-C(=O)-NRT1-, a group represented by the formula-NRT1-C(=O)-, a group represented by the formula-SO2-NRT1- or a group represented by the formula-NRT1-SO2-T3denotes hydrogen, C1-6alkyl, C3-6alkenyl, C3-6quinil, C3-10cycloalkyl, C6-10aryl, 5-10-membered heteroaryl or 4-10-membered non-aromatic heterocyclic group, and RT1denotes hydrogen or C1-6alkyl.

Each group of replacement of group B may be substituted by the Deputy selected from foster group C.

The replacement value of the group C

Substitute group C includes halogen, hydroxyl, mercapto, nitro, cyano, oxo, C1-6alkyl, C2-6alkenyl, C2-6quinil, C3-10cycloalkyl, C6-10aryl, 5-10-membered heteroaryl, 3-10-membered nonaromatic heterocyclic group, a C1-6Alcock and and C 1-6alkylthio.

The replacement value of the group D

Replacement group D includes amino, mono-C1-6alkylamino and di-C1-6alkylamino.

The replacement value group E

Replacement group E includes halogen, hydroxyl, mercapto, cyano, formyl, oxo, C1-6alkyl, C3-10cycloalkyl, C1-6alkoxy, amino, mono-C1-6alkylamino, di-C1-6alkylamino, azetidine, pyrrolidine, piperidinyl, piperazinil, diazepan and a group represented by the formula-T4-T5where T4denotes a carbonyl or sulfonyl, and T5represents C1-6alkyl, C3-10cycloalkyl, azetidine, pyrrolidine, piperidinyl, hydroxyl, C1-6alkoxy, amino, mono-C1-6alkylamino or di-C1-6alkylamino.

Each group from foster group E may be substituted by hydroxyl, C1-6the alkyl, CI-C1-6alkylamino, azetidinol or pyrrolidinium.

The replacement value of the group E'

Replacement group E' includes methyl, ethyl, dimethylamino, azetidine, pyrrolidine, piperidinyl and piperazinil.

Each group from foster group E may be substituted by hydroxyl, stands, dimethylamino, azetidinol or pyrrolidinium.

The replacement value group E"

Replacement group E" includes methyl, ethyl, n-propyl, acetyl, dimethylamino, diethylamino, azetidine is, pyrrolidinyl and piperazinil.

Each group from foster group E may be substituted by stands or dimethylamino.

The value of R2and R3

R2and R3denote hydrogen.

The value of R4, R5, R6and R7

R4, R5, R6and R7may be the same or different and each of them may denote hydrogen, halogen, hydroxyl, cyano, trifluoromethyl, C1-6alkyl, C2-6alkenyl, C2-6quinil, C1-6alkoxy, amino, mono-C1-6alkylamino, di-C1-6alkylamino or a group represented by the formula-CO-R12where R12denotes hydrogen, hydroxyl, C1-6alkyl, C1-6alkoxy, amino, mono-C1-6alkylamino or di-C1-6alkylamino.

Preferred examples of R4, R5, R6and R7include hydrogen, halogen, C1-6alkyl, C1-6alkoxy and trifluoromethyl.

More preferred examples of R4, R5, R6and R7include hydrogen, halogen and C1-6alkyl.

Even more preferred examples of R4, R5, R6and R7include the hydrogen, fluorine, chlorine and methyl.

R4, R5, R6and R7may be present in any of the following combinations: (1) they all represent hydrogen, (2) they represent substituents other than hydrogen, and (3) some and what they denote hydrogen, while others represent substituents other than hydrogen. Preferably from 2 to 4 of R4, R5, R6and R7denote hydrogen.

Preferred examples of the group represented by the formula:

include groups represented by the formulas:

The value of R8

R8denotes hydrogen or C1-6alkyl.

Preferred examples of R8include hydrogen.

The value of R9

R9represents C1-6alkyl, C2-6alkenyl, C2-6quinil, C3-10cycloalkyl, C6-10aryl, C3-10cycloalkyl-C1-6alkyl, C6-10aryl-C1--6alkyl, C1-6alkoxy, 5-10-membered heteroaryl, 3-10-membered nonaromatic heterocyclic group, a 5-10 membered heteroaryl-C1-6alkyl, 3-10-membered nonaromatic heterocyclic-C1-6alkyl or a group represented by the formula-NR11aR11bwhere R11aand R11bhave the above value.

R9may be substituted by the Deputy selected from foster group or A substitutional group B.

The value V1

V1denotes an oxygen or sulphur.

Preferred examples V1include oxygen.

The value V2

V2denotes an oxygen or sulphur.

The value W

W seat the et group, represented by the formula-N(RW3)-, where RW3denotes hydrogen or C1-6alkyl.

Preferred examples of W include a group represented by the formula-NH-.

Preferred combinations of W and V2include:

(1) combination, where W denotes a group represented by formula-N(RW3)-and V2denotes sulfur, where RW3has the above meaning; and

(2) combination, where W denotes a group represented by formula-N(RW3)-and V2denotes oxygen, where RW3has the above value.

Preferred combinations include:

(1) combination, where W denotes a group represented by the formula-NH-and V2denotes sulfur; and

(2) combination, where W denotes a group represented by the formula-NH-and V2denotes oxygen.

Preferred examples of R9include C1-6alkyl, C3-10cycloalkyl, C3-10cycloalkyl-C1-6alkyl, C6-10aryl-C1-6alkyl, 5-10-membered heteroaryl-C1-6alkyl and 3-10-membered nonaromatic heterocyclic-C1-6alkyl, and R9may be substituted by the Deputy selected from foster group or A substitutional group B.

More preferred examples of R9include C3-10cycloalkyl-C1-6alkyl and C6-10aryl-C1-6alkyl, and R9may be substituted by the Deputy, selected from foster group or A substitutional group B.

Even more preferred examples of R9include C3-10cycloalkyl-C1-6alkyl and C6-10aryl-C1-6alkyl, and R9may be substituted by the Deputy selected from foster group F, where the substituting group F includes halogen, trifluoromethyl, cyano, C1-6alkyl and C1-6alkoxy.

Particularly preferred examples of R9include cyclopentylmethyl, cyclohexylmethyl, cycloheptylmethyl, norbornane-2-ylmethyl and benzyl, and R9may be substituted by the Deputy selected from foster group F.

The value of X

X denotes a group represented by formula-C(R10)=or nitrogen, where R10denotes hydrogen, halogen, cyano, C1-6alkyl, C2-6alkenyl, C2-6quinil or a group represented by the formula-CO-R12where R12has the above value.

Preferred examples of X include a group represented by formula-C(R10a)=or nitrogen, where R10adenotes hydrogen, halogen or cyano.

Preferable examples of X include a group represented by the formula-CH=or nitrogen.

The Y value

Y represents oxygen, sulfur, sulfinil, sulfonyl or a group represented by formula-N(RY)-, where RYdenotes hydrogen or C1-6alkyl.

Preferred examples of Y include oxygen or a group represented by the formula-NH-.

More preferred examples of Y include oxygen.

The preferred compound of the present invention represented by the formula (I)includes the compound represented by the following formula (I-1):

R1and X have the same meaning as in the above formula (I).

The value W10

W10refers to a group represented by the formula:

left link connects a group-NH-, and the right link connects the group with R90.

The value of R40, R50and R60

R40, R50and R60may be the same or different and each denotes hydrogen, halogen or C1-6alkyl.

Preferably R40, R50and R60may be the same or different and each denotes hydrogen, fluorine, chlorine or methyl.

More preferably each of R40and R50denotes hydrogen, fluorine, chlorine or methyl, and R60denotes hydrogen.

The value of R90

R90represents C1-6alkyl, C3-10cycloalkyl, C6-10aryl, 5-10-membered heteroaryl, C3-10cycloalkyl-C1-6alkyl, C6-10aryl-C1-6alkyl or 5-10-membered heteroaryl-C1-6Ala is L. R90may be substituted by the Deputy selected from foster group F, where the substituting group F includes halogen, trifluoromethyl, cyano, C1-6alkyl and C1-6alkoxy.

Preferred examples of R90include C3-10cycloalkyl-C1-6alkyl and C6-10aryl-C1-6alkyl, and R90may be substituted by the Deputy selected from foster group F.

More preferred examples of R90include cyclopentylmethyl, cyclohexylmethyl, cycloheptylmethyl, norbornane-2-ylmethyl and benzyl, and R90may be substituted by the Deputy selected from foster group F.

A preferred compound of formula (I) includes a compound obtained by selecting suitable options R1, R2, R3, R4, R5, R6, R7, R8, R9, V1, V2, W, X and Y and arbitrary joins.

A preferred compound of formula (I-1) includes the compound obtained in the result of the selection of suitable R1, R40, R50, R60, R90, W10and X and arbitrary joins.

Specific examples of preferred compounds of formula (I) or formula (I-1) include example 3, example 13, example 22, example 28, example 38 example 39, example 52, the example 100, the sample 170, the example 172, example 174, example 78, example 179, 180 example 181, example 182, example 183, example 184 example 185, example 188 example 189 example 190, the example 191 example 192 example 193, example 194 example 195, example 196, example 201, example 208, the example 209, example 219, the example 221, example 223, example 224, the example 225, the example 245, example 246, example 250, the example 254, example 258, example 261, example 281, example 285, example 288, example 289, example 290, example 301, the example 309, example 311, the example 312, the example 314, the example 322, the example 326, the example 327, example 329, example 330, the example 331, example 334, example 335, the example 337, the example 339, the example 340, the example 341, example 342, example 343, example 344, example 345, the example 346, example 347, example 349, example 353, example 354, example 362, example 364, example 373, example 376, example 377, example 381 example 383, example 387, the example 389, example 390, example 391, the example 392, example 393, example 394, example 395, the example 396, example 397 and example 398.

The phrase "may be replaced by Deputy, selected from foster group" or "optionally substituted Deputy selected from foster group" means "may be substituted by 1-3 substituents arbitrarily selected from the substituents included in the replacement group.

The compound of the present invention has inhibitory activity against tyrosinekinase HGFR (examples of pharmacological tests 1 and 3) and, therefore, inhibits the proliferation of cancer cells, initiated by the activation of HGFR (example Farmak the logical analysis 2) and therefore exhibits inhibitory activity against tumor proliferation (example pharmacological analysis). The compound of the present invention also inhibits the migration of human cancer cells (example pharmacological analysis 4). In addition, the compound of the present invention inhibits the proliferation of endothelial cells of blood vessels and the formation of tubules from the data cells, a process mediated signal HGF-HGFR (examples pharmacological analysis 6 and 7).

Described that overexpression of HGFR is associated with malignant cancer tissues (excessive growth, invasion and growth of metastasis in cancer of the pancreas, stomach cancer, cancer of the colon, rectum, breast cancer, prostate cancer, lung cancer, kidney cancer, brain cancer, ovarian cancer and cancer of the blood (Cancer Research, 54, 5775-5778 (1994); Biochemical and Biophysical Research Communication, 189, 227-232 (1992); Oncogene, 7, 181-185 (1992); Cancer, 82, 1513-1520 (1998); J. Urology, 154, 293-298 (1995); Oncology, 53, 392-397 (1996); Oncogene, 14, 2343-2350 (1999); Cancer Research, 57, 5391-5398 (1997); Pathology Oncology Research, 5, 187-191 (1999); Clinical Cancer Research, 9, 181-187 (2003)).

It also describes that HGFR activation in endothelial cells of blood vessels contributes to tumor angiogenesis (Advances in Cancer Research, 67, 257-279 (1995)).

Therefore, the connection of the present invention, which has a high inhibitory activity against HGFR, can be used as protivoop Evoe means, angiogenesis inhibitor or inhibitor of cancer metastasis in different types of cancer, such as pancreatic cancer, stomach cancer, cancer of the colon, rectum, breast cancer, prostate cancer, lung cancer, kidney cancer, brain cancer and ovarian cancer.

The BEST WAY of carrying out the INVENTION

A common way to obtain

The compound of the present invention can be obtained by using the following methods. However, methods for obtaining compounds of the present invention is not limited to the described in this document.

The method of obtaining 1

The way to obtain the intermediate compounds (1m) and (1n)

A method of obtaining a 1-A

The way to obtain the intermediate compounds (1m) and (1n) by reacting a derivative of 2-aminopyridine or 6-aminopyrimidine with a derivative of phenol, thiophenol or aniline

The following diagram Y1denotes oxygen, sulfur or a group of formula-N(RY1)-, where RY1denotes hydrogen or C1-6alkyl; L1denotes a leaving group; R101represents C1-6alkyl or benzyl; R102represents C1-6alkyl, benzyl or 2-(trimethylsilyl)ethyl; R80represents C1-6alkyl; P represents a protective group for amino group; and other symbols have the above values.

The compound (1a) including the AET in itself, for example, ether 4-NITROPHENOL acid, ether 4-chloropicolinic acid, ester of 6-chloropyrimidine-4-carboxylic acid. Ether 4-NITROPHENOL acid and ether 4-chloropicolinic acid can be obtained by the esterification of 4-NITROPHENOL acid and 4-chloropicolinic acid, which are both commercially available (see the example of getting 111). Methyl 6-chloropyrimidine-4-carboxylate as one of the esters of 6-chloropyrimidine-4-carboxylic acid, described in Ukr. Kihm. Zh., 1982, Vol.48, p 67 (CAS No. 6627-22-1). Ether 6-chloropyrimidine-4-carboxylic acid can also be obtained by the method described in J. Heterocycl. Chem., 1, 130 (1964).

The compound (1d) includes, for example, such commercially available compounds as 2-amino-4-chloropyridine and 4-amino-6-chloropyrimidine. The compound (1d) can also be obtained by using method 1A-1, method 1A-2 and method 1A-3, described below, using the compounds (1a) as the starting material.

The compound (1f) includes, for example, such commercially available compounds as p-methylaminophenol and N-methyl-1,4-phenylenediamine, the dihydrochloride.

The compound (1e) can be obtained by protecting groups represented by the formula, R80NH-, the compound (1f). You can use the General reaction of the protection of the amino group. For example, the compound (1e) can be obtained by reacting compound (1f) with ethyl-chloroformate, methylchloroform benzylchloride, di-tert-BUTYLCARBAMATE or anhydride triperoxonane acid.

The compound (1g) includes, for example, such commercially available compounds as acetaminophen, N-(hydroxyphenyl)formamide, 4-(N-tert-butoxycarbonylamino)phenol, 4-triftoratsetofenona, 4-acetamidophenol, 4-(methylcarbamyl)aniline and 4-(tert-butylcarbamoyl)aniline.

The compound (1h) includes, for example, such commercially available compounds as 4-NITROPHENOL, 2-chloro-4-NITROPHENOL, 2-fluoro-4-NITROPHENOL, 3-fluoro-4-NITROPHENOL, 3-methyl-4-NITROPHENOL, 4-nitrothiophene, 4-nitroaniline and 2-methoxy-4-nitroaniline.

The compound (1i) includes, for example, such commercially available compounds as 4-aminophenol, hydrochloride 4-amino-3-chlorophenol, 4-amino-2,5-dimethylphenol, 4-amino-2,6-dichlorophenol, 5-amino-2-hydroxybenzonitrile, 4-aminothiophenol, p-phenylenediamine and 2,5-diaminoanisole.

The above compounds can also be obtained from commercially available compounds by known methods.

Method 1A-1

This method is a method of obtaining compound (1b) from the compound (1a). For example, you can use the hydrolysis in the presence of a base. As a basis you can use inorganic base such as sodium hydroxide, potassium hydroxide and lithium hydroxide. As a solvent it is possible to use methanol, tanol, water and the like, the reaction Temperature is in the range from 0°C to the boiling temperature under reflux. The reaction time ranges from 10 minutes to 30 hours.

Method 1A-2

This method is a method of rearrangement of the compound (1b) to obtain compound (1c). The compound (1c) can be obtained by reacting compound (1b) with an alcohol represented by the formula, R102-OH, in the presence of diphenylphosphinite and triethylamine. Preferred examples of R102include tert-butyl, benzyl and 2-(trimethylsilyl)ethyl. The solvent can be used N,N-dimethylformamide, N-organic, toluene and the like, as well as tert-butanol or benzyl alcohol. The reaction temperature ranges from room temperature to the boiling temperature under reflux. The reaction time ranges from 10 minutes to 30 hours.

Method 1A-3

This method is a method of obtaining compound (1d) from compound (1c) by carbamazepine. For this reaction it is possible to use a common method of removing protection from an amino group, specific examples of which include the removal of the protective group using acid such as hydrochloric acid, and triperoxonane acid, removing the protective group using inorganic bases, Taco is about as sodium hydroxide and potassium hydroxide, and removing the protective group using tetrabutylammonium fluoride. The solvent can be used methanol, ethanol, water, tetrahydrofuran, N,N-dimethylformamide and the like, the reaction Temperature is in the range from room temperature to the boiling temperature under reflux. The reaction time ranges from 10 minutes to 30 hours.

Method 1A-4, Method 1A-6, Method 1A-7, Method 1A-9, Method 1A-10

These ways are the ways of interaction of the compound (1d) with compounds (1e), (1f), (1g), (1h) and (1i) to obtain the compound (1j), (1n), (1k), (1l) or (1m), respectively. As a solvent it is possible to use N-organic, N,N-dimethylformamide, dimethylsulfoxide, 2-ethoxyethanol, chlorobenzene and the like In the reaction system, you can add a base or acid, namely, it is possible to use an organic base such as triethylamine and diisopropylethylamine, inorganic base such as potassium carbonate, cesium carbonate and sodium hydride, or an acid, such as hydrochloride of pyridine and hydrochloric acid. The reaction temperature ranges from room temperature to the boiling temperature under reflux. The reaction time ranges from 10 minutes to 30 hours.

Method 1A-5

This method is a method of removing protective groups link is (1j) to obtain the compound (1n). In this reaction it is possible to use a common method of removing protection from an amino group, a specific example of which is the removal of the protective group with an acid such as hydrochloric acid and triperoxonane acid, removing the protective group using inorganic bases such as sodium hydroxide and potassium hydroxide, and removing the protective group using tetrabutylammonium fluoride. If the protective group is benzyloxycarbonyl, and R4, R5, R6, R7and R10not denote chlorine, bromine and iodine, you can also use the removal of the protective group by catalytic hydrogenation using a catalyst of palladium on coal or palladium hydroxide. The solvent can be used methanol, ethanol, water, tetrahydrofuran, N,N-dimethylformamide and the like, the reaction Temperature is in the range from room temperature to the boiling temperature under reflux. The reaction time ranges from 10 minutes to 30 hours.

Method 1A-8

This method is a method of removing the protective group from the compound (1k) to obtain the compound (1m). You can use criteria such as those shown in Method 1A-5.

Method 1A-11

This method is a method of recovering nitrocompounds(1l) to obtain the compound (1m). You can use conditions, applied usually to restore the nitro group to the amino group, as a specific example of recovery using iron-ammonium chloride or iron-acetic acid. If R4, R5, R6, R7and R10not denote chlorine, bromine and iodine, you can also use the removal of the protective group by catalytic hydrogenation using a catalyst of palladium hydroxide or palladium on coal. The solvent can be used methanol, ethanol, water, N,N-dimethylformamide, ethyl acetate, tetrahydrofuran and the like, the reaction Temperature is in the range from room temperature to the boiling temperature under reflux. The reaction time ranges from 10 minutes to 30 hours.

Method 1A-12

This method is a method of alkylation of the compound (1m) to obtain the compound (1n). By reductive amination of the aldehyde or ketone can be obtained C1-6alkyl. As the reducing agent can be used sodium cyanoborohydride and sodium triacetoxyborohydride. As a solvent it is possible to use methanol, tetrahydrofuran, dichloromethane, dichloroethane, etc.

You can also use the recovery method benzotryazolyl derived by borohydride intothree is, described in Tetrahedron, 47(16), 2683(1991). For example, the compound (1n), in which R80denotes methyl, can be obtained by reduction with sodium borohydride derived benzotriazol-1-ylmethylamino resulting from the interaction of the compound (1m) with 1-(hydroxymethyl)-1H-benzotriazole. In the method of deriving benzotriazol-1-ylmethylamino as a solvent can be used an alcohol such as methanol or ethanol, or a mixture of alcohol with N,N-dimethylformamide, acetic acid or water. The reaction temperature is in the range from -5°C to the boiling temperature under reflux. The reaction time ranges from 10 minutes to 30 hours. In the method of recovering the sodium borohydride in a solvent can be used tetrahydrofuran, dioxane, alcohol, such as methanol or ethanol, or a mixture of alcohol with N,N-dimethylformamide and the like, the reaction Temperature is in the range from -5°C to the boiling temperature under reflux. The reaction time ranges from 10 minutes to 30 hours.

Method 1A-13

This method represents an alternative method of obtaining the compound (1j) by alkylation of the compound (1k) to obtain the compound (1j). The compound (1j) can be obtained by interaction with alkylhalogenide in the presence of such a base as potassium carbonate or guide the ID of sodium. The solvent can be used tetrahydrofuran, N,N-dimethylformamide and the like, the reaction Temperature is in the range from 0°C to the boiling temperature under reflux. The reaction time ranges from 10 minutes to 30 hours.

A method of obtaining a 1-B

Way to obtain the intermediate compound (1n) by reacting the ester of pyridine-2-carboxylic acid or ester pyrimidine-6-carboxylic acid derivatives of phenol, thiophenol or aniline

In this diagram, all the symbols have the above values.

Method 1B-1, Method 1B-2, Method 1B-3, Method 1B-4, Method 1B-5

These ways are the ways of interaction of the compound (1a) with the compound (1f), (1g), (1e), (1i) or (1h) to obtain the compound (1o), (1p), (1s), (1r) or (1q), respectively. You can use methods similar to those described in method 1A-4.

Method 1B-6

This method is a way to protect the amino group of the compound (1o) to obtain the compound (1s). You can use a common way to protect the amino group. For example, you can use the reaction with etelcharge.com, methylchloroform, benzylchloride, di-tert-BUTYLCARBAMATE and triperoxonane anhydride. In the reaction system, you can add a base, for example an organic base, such ka is pyridine, the triethylamine and diisopropylethylamine, and an inorganic base such as sodium carbonate, potassium carbonate and sodium bicarbonate. The solvent can be used tetrahydrofuran, acetone, water, dioxane and the like, the reaction Temperature is in the range from room temperature to the boiling temperature under reflux. The reaction time ranges from 10 minutes to 30 hours.

Method 1B-7

This method is a method of alkylation of the compound (1p) to obtain the compound (1s). You can use methods similar to those described in method 1A-13.

Method 1B-8

This method is a method of alkylation of the compound (1r) to obtain the compound (1o). You can use methods similar to those described in method 1A-12.

Method 1B-9

This method is a way to protect the amino group of the compound (1r) to obtain the compound (1p). You can use methods similar to those described in method 1B-6.

Method 1B-10

This method is a method of recovery of the nitro group of the compound (1q) to obtain the compound (1r). You can use methods similar to those described in method 1A-11.

Method 1B-11

This method is a method of obtaining compound (1t) from compound (1ps) (connection (1ps) is a compound (1p) or the compound (1s)described in the method is to obtain 1-B. You can use methods similar to those described in method 1A-1.

Method 1B-12

This method is a method of obtaining compound (1u) from the compound (1t). You can use methods similar to those described in method 1A-2.

Method 1B-13

This method is a way to remove the two protective groups, R102-O-C(=O)-" and "P", with the compound (1u) to obtain the compound (1n). Depending on the type of protective groups to obtain the compound (1n) you can use a suitable combination of the removal of the protective group with an acid such as hydrochloric acid and triperoxonane acid, removal of the protective group using inorganic bases such as sodium hydroxide and potassium hydroxide, removing the protective group using tetrabutylammonium fluoride, and the removal of the protective group by catalytic hydrogenation using a catalyst of palladium on coal or palladium hydroxide.

The method of obtaining 1B-14, the Method of obtaining 1B-16

These methods are ways, including the removal of the compound (1u) only one of the two protective groups "R102-O-C(=O)-" and "P" with obtaining the compound (1v) or the compound (1w), respectively. This method is applicable only if two protective groups "R102-O-C(=O)-" and "P" are different from each other. Nab is emer, if the group represented by the formula, R102-O-C(=O)- represents a 2-(trimethylsilyl)etoxycarbonyl, and P represents benzyloxycarbonyl, for the selective removal of one of the two protective groups, you can use the delete using tetrabutylammonium fluoride or the removal of the protective group by catalytic hydrogenation.

Method 1B-15

This method is a method of removing the protective group of the compound (1v) to obtain the compound (1n). You can use a method similar to that described in method 1A-5.

Method 1B-17

This method is a method of removing the protective group from the compound (1w) to obtain the compound (1n). You can use a method similar to that described in method 1A-5.

The method of obtaining 2

An alternative way to obtain the intermediate compound (1l), (1m), (1k), (1j) and (1n) of the pyridine or pyrimidine derivative (2a)containing a leaving group L14 position and a leaving group L2in the 2 or 6 position

This diagram L2denotes a leaving group. Other symbols have the above values.

The compound (2a) includes, for example, commercially available compounds such as 4,6-dichloropyrimidine, 2-chloro-4-nitropyridine and 2,4-dichloropyridine. The compound (2a) can also paragraph shall be obtained from commercially available compounds by known methods.

Method 2-1, the Method 2-2, the Method 2-3, 2-4 Way, Way 2-5

These ways are the ways of interaction of the compound (2a) from compound (1h), (1i), (1g), (1e) or (1f) to obtain the compound (2b), (2c), (2d), (2e) or (2f), respectively. Preferably in the compound (2a) L1means more reactive group than the L2. For example, L1may indicate a nitrogroup, and L2can refer to chlorine. In these ways, you can use methods similar to those described in method 1A-4.

How 2-6

This method is a method of recovery of the nitro group of the compound (2b) to obtain the compound (2c). You can use criteria that are traditionally used to restore the nitro group to the amino group. For example, you can use the recover in the presence of iron-ammonium chloride or iron-acetic acid. The solvent can be used methanol, ethanol, water, N,N-dimethylformamide, tetrahydrofuran and the like, the reaction Temperature is in the range from room temperature to the boiling temperature under reflux. The reaction time ranges from 10 minutes to 30 hours.

The way 2-7

This method is a way to protect the amino group of compound (2c) to obtain the compound (2d). You can use methods similar to those described in method 1B-6.

How 2-8

<> This method is a method of alkylation of the compound (2d) to obtain the compound (2e). You can use methods similar to those described in method 1A-13.

The way 2-9

This method is a way to protect the amino group of compound (2f) to obtain the compound (2e). You can use methods similar to those described in method 1B-6.

How 2-10

This method is a method of alkylation of compound (2c) to obtain the compound (2f). You can use methods similar to those described in method 1A-12.

How 2-11, the Way 2-12, the Way 2-13, Way 2-14, the Way 2-15

These methods are ways of turning the leaving group L2compound (2b), (2c), (2d), (2e) or (2f) in the amino group to obtain the compound (1l), (1m), (1k), (1j) or (1n), respectively. This method can be performed, for example, using ammonia-ethanol solution in a tightly closed tube. The reaction is carried out at the boiling temperature under reflux. The reaction time ranges from 10 minutes to 100 hours.

The method of obtaining 3

The method of obtaining an intermediate compound represented by formula (XI)

In this formula, W1denotes a direct bond, a group represented by formula-C(RW1)(RW2)-, or a group represented by the formula-NH-, R W1and RW2may be the same or different and each denotes hydrogen, halogen, C1-6alkyl or C1-6alkoxy; and the other symbols have the above values.

The method of obtaining 3-A

The method of obtaining the intermediate product (3a), where V2denotes sulfur, W1refers to a group represented by the formula-NH-, and R9means R9aalong with the intermediate product represented by the formula (XI)

In this diagram, R9arepresents C1-6alkyl, C2-6alkenyl, C2-6quinil, C3-10cycloalkyl, C6-10aryl, C3-10cycloalkyl-C1-6alkyl, C6-10aryl-C1-6alkyl, 5-10-membered heteroaryl, 3-10-membered nonaromatic heterocyclic group (limited group containing a bond between the carbon atom involved in the formation of a cycle), 5-10-membered heteroaryl-C1-6alkyl and 3-10-membered nonaromatic heterocyclic-C1-6alkyl, and R9amay be substituted by the Deputy selected from foster group or A substitutional group B and if R9acontains a hydroxyl or primary or secondary amino group as the replacement group replacement group may be protected by a suitable protecting group, and other symbols have the above values.

Method 3A-1

Dunn is the first method is a method of deriving ulltimately (3a) of the connection (1mn) (connection (1mn) denotes the compound (1m) or the compound (1n), described in [production method of 1-A], this notation is used below). In this way, for example, you can use the method of interaction arylisocyanate represented by the formula, R9a-C(=O)-NCS, with compound (1mn). In the reaction system, you can add the acid, such as camphorsulfonate. As a solvent it is possible to use a mixture of toluene and methanol, a mixture of toluene and ethanol, acetonitrile, N,N-dimethylformamide, and tetrahydrofuran. The reaction temperature ranges from room temperature to the boiling temperature under reflux. The reaction time ranges from 10 minutes to 30 hours. If hydroxyl, primary amino or secondary amino group, R9asecure deletion can be performed in any suitable way to obtain a final product.

Utilizationand represented by the formula, R9a-C(=O)-NCS, can be obtained as a result of interaction of acylchlorides represented by the formula, R9a-C(=O)-Cl, with potassium thiocyanate. The solvent can be used acetonitrile, ethyl acetate, and the like, the reaction Temperature is in the range from room temperature to the boiling temperature under reflux. The reaction time ranges from 10 minutes to 100 hours.

Method 3A-2

This method is a method of obtaining the soybean is inane (3b) from the compound (1w). You can use methods similar to those described in method 3A-1.

Method 3A-3

This method is a method of removing the protective group of the compound (3b) to obtain the compound (3a). You can use methods similar to those described in method 1A-5.

The method of obtaining 3-B

Way to obtain the intermediate compound (3f)represented by the formula (XI), where V2denotes oxygen, W1refers to a group represented by the formula-NH-, and R9means R9a.

In this diagram, the symbols have the above values.

Method 3B-1

This method is a method of deriving allodapini (3f) from the compound (1mn). In this way it is possible to use, for example, the interaction arylisocyanate represented by the formula, R9a-C(=O)-NCO, with the compound (1n). The solvent can be used N,N-dimethylformamide, tetrahydrofuran and the like, the reaction Temperature is in the range from 0°C to the boiling temperature under reflux. The reaction time ranges from 10 minutes to 30 hours. If hydroxyl, primary amino or secondary amino group, R9asecure deletion can be performed in any suitable way to obtain a final product.

Arylisocyanate represented by the formula, R9a-C(=O)-NCO, which you can get as a result of interaction of amide, represented by the formula, R9a-C(=O)-NH2with oxalylamino. The solvent can be used 1,2-dichloroethane and the like, the reaction Temperature is in the range from room temperature to the boiling temperature under reflux. The reaction time ranges from 1 hour to 100 hours.

Method 3B-2

This method is a method of deriving allodapini (3g) from the compound (1w). You can use methods similar to those described in method 3B-1.

Method 3B-3

This method is a method of removing the protective group from the compound (3g) to obtain the compound (3f). You can use methods similar to those described in method 1A-5.

The method of obtaining 3-C

Way to obtain the intermediate compound (3o)represented by the formula (XI), where V2denotes oxygen, W1denotes W2and W2denotes a direct bond, a group represented by formula-C(RW1)(RW2)-, where RW1and RW2may be the same or different and each denotes hydrogen, halogen, C1-6alkyl or C1-6alkoxy, and R9means R9b.

In this diagram, R103represents C1-6alkyl or benzyl; R9bindicates 3-10-membered nonaromatic heterocyclic group (limited group, with whom containing a series of the nitrogen atom in the cycle, moreover, the nitrogen has a connecting link), or a group represented by the formula-NR11aR11bwhere R11aand R11bhave the above significance, and R9bmay be substituted by the Deputy selected from foster group or A substitutional group B and if R9bas a substitute group contains a hydroxyl, primary amino or secondary amino group, this group may be protected by a suitable protecting group, and other symbols have the above values.

The compound (3k) includes, for example, commercially available compounds such as benzylmalonate and mono-benzyl 2-formulant.

The compound (3l) includes, for example, commercially available compounds such as ethyl malonyl chloride, methyl malonyl chloride, ethyl oxalicacid and methyl oxalicacid.

The above compounds can also be obtained from commercially available compounds by known methods.

Method 3C-1

This method is a way of condensing the compound (3k) with an amine represented by the formula, R9b-H or its salt to obtain the compound (3m). In this way it is possible to use a common method of condensation of carboxylic acids with amine. For example, the solvent can be used N,N-dimethylformamide and tetrahydrofuran, as well as condensing means m which should be used carbonyldiimidazole, dicyclohexylcarbodiimide, 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride, and hexaphosphate (1H-1,2,3-benzotriazol-1 iloxi)(three(dimethylamino))phosphonium. You can also use an organic base such as triethylamine. The reaction temperature is in the range from 0°C to the boiling temperature under reflux. The reaction time ranges from 10 minutes to 30 hours.

Method 3C-2

This method is a way of condensing the compound (3l) with an amine represented by the formula, R9b-H or its salt to obtain the compound (3m). The solvent can be used N,N-dimethylformamide, tetrahydrofuran, dichloromethane and the like, it is Also possible to use an organic base such as triethylamine. The reaction temperature is in the range from 0°C to the boiling temperature under reflux. The reaction time ranges from 10 minutes to 30 hours.

Method 3C-3

This method is a method of obtaining compound (3n) from compound (3m). This method can be performed using hydrolysis in the presence of a base. As a basis you can use the lithium hydroxide and the like, If R103denotes benzyl, and R9bdoes not contain chlorine, bromine and iodine as a substitute group, it is also possible to use catalytic hydrogenation in presets is under palladium on coal or palladium hydroxide as a catalyst. The solvent can be used methanol, ethanol, water, N,N-dimethylformamide, tetrahydrofuran, ethyl acetate, and the like, the reaction Temperature is in the range from 0°C to the boiling temperature under reflux. The reaction time ranges from 10 minutes to 30 hours.

Method 3C-4

This method is a way of condensing the compound (1mn) with compound (3n) to give the compound (3o). As the condensing means you can use 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride, hexaflurophosphate (1H-1,2,3-benzotriazol-1 iloxi)(three(dimethylamino))phosphonium etc. you can Also use an organic base such as triethylamine. The solvent can be used tetrahydrofuran, N,N-dimethylformamide and the like, the reaction Temperature is in the range from 0°C to the boiling temperature under reflux. The reaction time ranges from 10 minutes to 30 hours.

Method 3C-5 3C Way 6 Way 3C-10

These methods are methods of producing compounds (3p), (3q) or (3s) of the compound (1w), (1or) (connection (1or) denotes the compound (1o) or the compound (1r) described in [production method of 1-B], then use the same designation), or (2f), respectively. You can use methods similar to those described in method 3C-4.

Method 3C-7

This way p is ecstasy a method of obtaining compound (3r) from the compound (3q). You can use methods similar to those described in method 1A-1.

Method 3C-8

This method is a method of rearrangement of the compound (3r) to obtain the compound (3p). You can use methods similar to those described in method 1A-2.

Method 3C-9

This method is a method of removing the protective group from the compound (3p) to obtain the compound (3o). You can use methods similar to those described in method 1A-5.

Method 3C-11

This method is a way of turning the leaving group L2compounds (3s) in the amino group to obtain compound (3o). You can use methods similar to those described in method 2-11.

The method of obtaining 3-D

The method of obtaining the intermediate (3t)represented by the formula (XI), where V2denotes oxygen, W1refers to a group represented by the formula-NH-, and R9means R9b

In this diagram, the symbols have the above values.

The way 3D-1

This method is a method of obtaining compound (3t) from compound (1mn). You can use the method in which the compound (1mn) interacts with N-(chlorocarbonyl)isocyanate or phenylisocyanate and then with an amine represented by the formula, R9b-H, etc. can Also be used a base, such as diisopropyl is in and triethylamine. The solvent can be used dichloromethane, dichloroethane, tetrahydrofuran and the like, the reaction Temperature is in the range from 0°C to the boiling temperature under reflux. The reaction time ranges from 10 minutes to 30 hours.

The way 3D 2

This method is a method of obtaining compound (3u) from the compound (1w). You can use methods similar to those described in method 3D-1.

The way 3D-3

This method is a method of removing the protective group from the compound (3u) to obtain the compound (3t). You can use methods similar to those described in method 1A-5.

If the group represented by the formula, R9bcontains as a substitute group of the amino group or hydroxyl, or if Y1refers to a group represented by the formula-NH-, can be protected in a suitable manner using any of the methods previously described and the protective group may be removed by any suitable method.

The method of obtaining 4

The method of synthesis of various intermediates, alternative method of obtaining 3-C

In this diagram, the symbols have the above values.

How 4-1, the Method 4-4, 4-7 Way, Way 4-10

These methods are a way of condensation of compounds (1mn), (1w), (1or) or (2f) with compound (3k) to obtain the compounds (4a), (4c), (4e) or (4g) respectively. You can use the method described in method 3C-4.

How 4-2, Fashion 4-5, 4-8 Way, Way 4-11

These methods are methods of producing compounds (4b), (4d), (4f) or (4h) of the compounds (4a), (4c), (4e) or (4g) respectively. You can use methods similar to those described in method 1A-1. However, in the method of 4-5 and 4-8 way the removal of the protective groups is carried out in conditions that allow you to save a protective group of an amino group or carboxyl group in the 2 position of the pyridine. For example, if R101or R102denote C1-6alkyl or 2-(trimethylsilyl)ethyl, and R103denotes benzyl, can be catalytic hydrogenation to obtain the compound (4d) and (4f).

How 4-3, Fashion 4-6, the Way 4-9, the Way 4-12

These methods are a way of condensation of compounds (4b), (4d), (4f) or (4h) with an amine represented by the formula, R9b-H or its salt to obtain the compound (3o), (3p), (3q) or (3s), respectively. You can use a method similar to that described in method 3C-1.

The method of obtaining 5

Way to obtain the intermediate compound (5f)

In this scheme, RW3denotes hydrogen or C1-6alkyl, and other symbols have the above values.

The compound (5a) can be obtained from the amine represented by the formula, R W3-NH, and phenylcarbamate or penishealthinformation according to the method described in WO 02/32872 (method of obtaining 16, an example of a method of obtaining 316-1 or an example of a method of obtaining 316-2), or by the method described in J. Org. Chem., 2000, 65(19), 6237. As an amine represented by the formula, RW3-NH, you can use a commercially available connection.

The compound (5b) can be obtained by reacting carboxylic acid represented by the formula, R9a-C(=O)-OH with thionyl chloride, etc. as a carboxylic acid represented by the formula, R9a-C(=O)-OH, you can use a commercially available connection.

How 5-1

This method is a method of obtaining compound (5c) from the compound (5a) by acylation using the compound (5b). The solvent can be used tetrahydrofuran, benzene, toluene, xylene, chlorobenzene and the like can Also be used a base such as sodium hydride, pyridine and triethylamine. The reaction temperature is in the range from 0°C to the boiling temperature under reflux. The reaction time ranges from 10 minutes to 30 hours.

Method 5-2, the Way 5-3

These methods are methods of obtaining compound (5f) and (5g) by reacting compound (1mn) or (1w) with compound (5c), respectively. As a solvent, you can use the ü N,N-dimethylformamide, dimethyl sulfoxide, N-organic, tetrahydrofuran, etc. can Also be used a base such as sodium hydride, pyridine and triethylamine. The reaction temperature is in the range from 0°C to the boiling temperature under reflux. The reaction time ranges from 10 minutes to 30 hours.

If the group represented by the formula, R9acontains as a substitute group of the amino group or hydroxyl, or if Y1refers to a group represented by the formula-NH-, can be protected in a suitable manner using any of the methods previously described and the protective group may be removed by any suitable means, respectively.

The way 5-4

This method is a method of removing the protective group from the compound (5g) to obtain the compound (5f). You can use methods similar to those described in method 1A-5.

The method of obtaining 6

Way to obtain the intermediate compound (6c)

In this diagram, the symbols have the above values.

The compound (6a) can be obtained by using the reaction of formation of urea, which involves amine represented by the formula, RW3-NH, and the amine represented by the formula, R9b-H. Compound can be obtained according to the method described in Synthesis, 1189 (1997). As an amine represented by the formula, RW3 -NH, and an amine represented by the formula, R9b-H, you can use a commercially available connection.

The way 6-1

This method is a method of obtaining compound (6b) from the compound (6a). As a reagent use phenylcarbamate or phenyl chlorothionoformate. The solvent can be used tetrahydrofuran, benzene, toluene, xylene, chlorobenzene and the like can Also be used a base such as sodium hydride, pyridine and triethylamine. The reaction temperature is in the range from 0°C to the boiling temperature under reflux. The reaction time ranges from 10 minutes to 30 hours.

How 6-2, 6-3 Way

These methods are ways of interacting compounds (1mn) or (1w) with compound (6b) to obtain the compound (6c) or (6d), respectively. The solvent can be used N,N-dimethylformamide, dimethylsulfoxide, N-organic, tetrahydrofuran, etc. can Also be used a base such as sodium hydride, pyridine and triethylamine. The reaction temperature is in the range from 0°C to the boiling temperature under reflux. The reaction time ranges from 10 minutes to 30 hours.

If the group represented by the formula, R9bcontains as a substitute group of the amino group or hydroxyl, or if Y1about the mean group represented by the formula-NH-, can be protected in a suitable manner using any of the methods previously described and the protective group may be removed by any suitable means, respectively.

How 6-4

This method is a method of removing the protective group from the compound (6d) to obtain the compound (6c). You can use methods similar to those described in method 1A-5.

The method of obtaining 7

The method of obtaining an intermediate compound represented by formula (XII)

In this formula the symbols have the above values.

The way to obtain 7-A

Way to obtain the intermediate compound (7e), which is an intermediate compound represented by formula (XII), where R1means R1a

In this diagram, R1aindicates 3-10-membered nonaromatic heterocyclic group (limited group containing a nitrogen atom in the cycle, and the nitrogen forms a connecting link), or a group represented by the formula-NR11aR11bwhere each of R11aand R11bhas the above significance, and R1amay be substituted by the Deputy selected from foster group or A substitutional group B, and, if R1acontains as a replacement of the hydroxyl group, PHE is a primary amino group or secondary amino group, such a group can be protected with suitable protective group; and other symbols have the above values.

Method 7A-1, 7A Way, 2-Way 7A-3, 7A Way, 4-Way 7A-5

These methods are the methods of obtaining the compounds (7a), (7b), (7c), (7d) and (7e) of the compound (1l), (1m), (1k), (1j) or (1n), respectively. For example, you can use the method in which the compound (1l), (1m), (1k), (1j) or (1n) turn broadcast carbamino acid or thioester derivative of carbamino acid using the compound represented by the formula Ar-OC(=O)-Cl, where Ar denotes a phenyl group optionally substituted by one or two substituents selected from halogen, methyl, methoxy and nitro, or a compound represented by the formula Ar-OC(=S)-Cl, where Ar has the above meaning, with subsequent interaction with the amine. Alternatively, the compound (1l), (1m), (1k), (1j) or (1n) can interact with urethane derivative, THIOCARBAMATE derivatives, isocyanate derivative or isothiocyanates derived by transformation into the corresponding derivative of urea or thiourea. The solvent can be used chloroform, toluene, N-organic, N,N-dimethylformamide, dimethylsulfoxide, chlorobenzene, etc. you can Also use a mixture of the above solvent and water. You can also use the base. Namely, you can use the with organic base, such as pyridine, triethylamine and diisopropylethylamine, and an inorganic base such as potassium carbonate, cesium carbonate, sodium hydride and sodium hydroxide. The reaction temperature is in the range from 0°C to the boiling temperature under reflux. The reaction time ranges from 10 minutes to 30 hours.

After completion of the way of a replacement group for R1acan be modified by conventional reactions such as oxidation, reduction, complex etherification, amidation, introduction of a protective group, removing the protective groups and hydrolysis, which are carried out using appropriate methods. For example, a method that involves the interaction of the compound (1l), (1k) or (1j) with a ketone or aldehyde-containing amine, followed by reductive amination of the amine with an introduction to R1aamino-containing side chain. As the reducing agent can be used cyanoborohydride sodium, triacetoxyborohydride sodium, etc. as a solvent can be used methanol, tetrahydrofuran, dichloromethane, dichloroethane, etc. in Addition, the compound (1l), (1k) or (1j) can be subjected to interaction with the amine containing ester, to obtain the compounds of the ester fragment of which is hydrolized in the presence of a base such as lithium hydroxide, hydroxide n the sodium and potassium hydroxide, in ethanol containing water, with subsequent transformation under the action of the condensing means in the amide derivative. The solvent can be used N,N-dimethylformamide, tetrahydrofuran, etc. as a condensing means you can use 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride and hexaflurophosphate (1H-1,2,3-benzotriazol-1 iloxi)(three(dimethylamino))phosphonium. The reaction temperature is in the range from 0°C to the boiling temperature under reflux. The reaction time ranges from 10 minutes to 30 hours.

Method 7A-6

This method presents a way to restore the connection (7a) to obtain the compound (7b). You can use methods similar to those described in method 1A-11.

Method 7A-7

This method is a way to protect the amino group of compound (7b) to obtain the compound (7c). You can use methods similar to those described in method 1B-6.

Method 7A-8

This method is a method of alkylation of the compound (7c) to obtain the compound (7d). You can use methods similar to those described in method 1A-13.

Method 7A-9

This method is a method of removing the protective group from the compound (7d) to obtain the compound (7e). You can use methods similar to those described in method 1A-5.

Method 7A-10

This way PR is dstanley a method of alkylation of the compound (7b) to obtain the compound (7e). You can use methods similar to those described in method 1A-12.

The way to obtain 7-B

Way to obtain the intermediate compound (7j)represented by the formula (XII), where R1means R1b

In this diagram, R1brepresents C1-6alkyl, C2-6alkenyl, C2-6quinil, C3-10cycloalkyl, C6-10aryl, C3-10cycloalkyl-C1-6alkyl, C6-10aryl-C1-6alkyl, 5-10-membered heteroaryl, 3-10-membered nonaromatic heterocyclic group (limited group containing a link connecting this group with the carbon atom participating in the education cycle), 5-10-membered heteroaryl-C1-6alkyl and 3-10-membered nonaromatic heterocyclic-C1-6alkyl, and R1bmay be substituted by the Deputy selected from foster group or A substitutional group B and if R1bcontains a hydroxyl or primary or secondary amino group as the replacement group replacement group may be protected by a suitable protecting group; and other symbols have the above values.

Method 7B-1, 7B Way, 2-Way 7B-3 7B Way, 4-Way 7B-5

These methods are the methods of obtaining the compound (7f), (7g), (7h), (7i) (7j) of the compound (1l), (1m), (1k), (1j) or (1n), respectively. Namely, you can use the way in to the m compound (1l), (1m), (1k), (1j) or (1n) interacts with acylchlorides, carboxylic anhydride or diacylglycerol, or the manner in which the compound (1l), (1m), (1k), (1j) or (1n) interacts with the carboxylic acid in the presence of a condensing means, such as hexaflurophosphate (1H-1,2,3-benzotriazol-1 iloxi)(three(dimethylamino))phosphonium, to obtain the compound (7f), (7g), (7h), (7i) or (7j), respectively. In addition, to get thioamide derived, it is possible to synthesize amide derivative, which is then converted into thioamide using reagent Losson (Org. Synth., 1990, VII, 372; J. Org. Chem., 1990, 55(14), 4484). The solvent can be used tetrahydrofuran, chloroform, toluene, N-organic, N,N-dimethylformamide, dimethylsulfoxide, chlorobenzene, etc. you can Also use a base, e.g. an organic base such as pyridine, triethylamine and diisopropylethylamine, and an inorganic base such as potassium carbonate, cesium carbonate and sodium hydride. The reaction temperature is in the range from 0°C to the boiling temperature under reflux. The reaction time ranges from 10 minutes to 30 hours.

After completion of the way of a replacement group for R1bcan be modified by conventional reactions such as oxidation, reduction, complex etherification, amidation, introduction of protective groups, Alenia protective groups and hydrolysis, conducted using appropriate methods, as described in method 7A-1 the above method of producing 7-A.

Method 7B-6

This method is a method of recovery of the compound (7f) to obtain the compound (7g). You can use methods similar to those described in method 1A-11.

Method 7B-7

This method is a way to protect the amino group of compound (7g) to obtain the compound (7h). You can use methods similar to those described in method 1B-6.

Method 7B-8

This method is a method of alkylation of the compound (7h) to obtain the compound (7i). You can use methods similar to those described in method 1A-13.

Method 7B-9

This method is a method of removing the protective group from the compound (7i) to obtain the compound (7j). You can use methods similar to those described in method 1A-5.

Method 7B-10

This method is a method of alkylation of the compound (7g) to obtain the compound (7j). You can use methods similar to those described in method 1A-12.

The way to obtain 7-C

The method of obtaining the intermediate (7o)represented by the formula (XII), where R1means R1c

In this diagram, R1crepresents C1-6alkoxy, and R1cmay be substituted by the Deputy, is gathered from foster group or A substitutional group B, and if R1ccontains a hydroxyl or primary or secondary amino group as the replacement group replacement group may be protected by a suitable protecting group; and other symbols have the above values.

Method 7C-1, 7C Way, 2-Way 7C-3, 7C Way, 4-Way 7C-5

These methods are methods of producing compounds (7k), (7l), (7m), (7n) or (7o) of the compound (1l), (1m), (1k), (1j) or (1n), respectively. The compound (1l), (1m), (1k), (1j) or (1n) can interact with the ether chlorocarbonic acid, tieferen chlorocarbonic acid, dialkyldithiocarbamato etc. with obtaining compounds (7k), (7l), (7m), (7n) or (7o). You can also use the base, organic base, such as pyridine, triethylamine and diisopropylethylamine, and an inorganic base such as potassium carbonate, cesium carbonate and sodium hydroxide. The solvent can be used tetrahydrofuran, chloroform, dichloroethane, N,N-dimethylformamide, dimethylsulfoxide, chlorobenzene, etc. you can Also use a mixture of the above solvent and water. The reaction temperature is in the range from 0°C to the boiling temperature under reflux. The reaction time ranges from 10 minutes to 30 hours.

After completion of the way of a replacement group for R1ccan be modified by conventional reactions, t is such as oxidation, recovery complex etherification, amidation, introduction of a protective group, removing the protective groups and hydrolysis, which are carried out using appropriate methods, as described in method 7A-1 the above method of producing 7-A.

Method 7C-6

This method presents a way to restore the connection (7k) to obtain the compound (7l). You can use methods similar to those described in method 1A-11.

Method 7C-7

This method is a way to protect the amino group of compound (7l) obtaining compounds (7m). You can use methods similar to those described in method 1B-6.

Method 7C-8

This method is a method of alkylation of the compound (7m) to obtain the compound (7n). You can use methods similar to those described in method 1A-13.

Method 7C-9

This method is a method of removing the protective group from the compound (7n) to obtain the compound (7o). You can use methods similar to those described in method 1A-5.

Method 7C-10

This method is a method of alkylation of the compound (7l) obtaining compounds (7o). You can use methods similar to those described in method 1A-12.

The way to obtain 8

The method of obtaining the compounds of the present invention represented by the formula (I)

In this formula IC is s have the above values.

This diagram Y2means sulfinil or sulfonyl; and other symbols have the above values.

The way 8-1

This method is a method of obtaining the compound (I-A) of the present invention from the compound (8a), that is, the above intermediate compound (XI).

(1) If R1or R9not contain a hydroxyl, primary or secondary amino group, and when Y represents a group other than the group represented by the formula-NH-:

Method 1

Using the compound represented by the formula Ar-OC(=O)-Cl, where Ar has the above meaning, compounds represented by the formula Ar-OC(=S)-Cl, where Ar has the above meaning, and the like, compound (8a) can be transformed into the ether derivative of carbamino acid or thioester derivative of carbamino acid, which is then subjected to interaction with the amine to obtain the compound (I-A) of the present invention. Alternatively, the compound (8a) can interact with urethane derivative, THIOCARBAMATE derivatives, isocyanate derivative or isothiocyanates derived from the formation of compound (I-A) of the present invention. The solvent can be used chloroform, toluene, N-organic, N,N-dimethylformamide, dimethylsulfoxide, chlorobenzene, etc. you can Also use the with a mixture of the above solvents with water. You can also use the base, organic base, such as pyridine, triethylamine and diisopropylethylamine, and an inorganic base such as potassium carbonate, cesium carbonate, sodium hydride and sodium hydroxide. The reaction temperature is in the range from 0°C to the boiling temperature under reflux. The reaction time ranges from 10 minutes to 30 hours.

Method 2

Compound (8a) can interact with acylchlorides, carboxylic acid anhydride, diacylglycerol etc. with obtaining the compound (I-A) of the present invention. Alternatively, the compound (8a) can interact with the carboxylic acid in the presence of a condensing means, such as hexaflurophosphate (1H-1,2,3-benzotriazol-1 iloxi)(three(dimethylamino))phosphonium obtaining the compound (I-A) of the present invention. The solvent can be used tetrahydrofuran, chloroform, toluene, N-organic, N,N-dimethylformamide, dimethylsulfoxide, chlorobenzene, etc. you can Also use the base, organic base, such as pyridine, triethylamine and diisopropylethylamine, and an inorganic base such as potassium carbonate, cesium carbonate and sodium hydride. The reaction temperature is in the range from 0°C to the boiling temperature under reflux. The reaction time is titsa in the interval from 10 minutes to 30 hours.

Method 3

Compound (8a) can interact with the ether chlorocarbonic acid, tieferen chlorocarbonic acid or dialkyldithiocarbamato with obtaining the compound (I-A) of the present invention. You can also use the base, organic base, such as pyridine, triethylamine and diisopropylethylamine, and an inorganic base such as potassium carbonate, cesium carbonate and sodium hydroxide. The solvent can be used tetrahydrofuran, chloroform, dichloroethane, N,N-dimethylformamide, dimethylsulfoxide, chlorobenzene, etc. you can Also use a mixture of the above solvents with water. The reaction temperature is in the range from 0°C to the boiling temperature under reflux. The reaction time ranges from 10 minutes to 30 hours.

(2) If R1or R9contains a hydroxyl, primary or secondary amino group, or if Y1refers to a group represented by the formula-NH-:

After appropriate protection of the above substituents can be the above-described reaction with the subsequent removal of the protective groups suitable means and obtaining the compound (I-A) of the present invention.

(3) After completion of the way of a replacement group for R1or R9can be modified by conventional reactions such as oxidation, restoring the people, complex etherification, amidation, introduction of a protective group, removing the protective groups and hydrolysis, which are carried out using appropriate methods, as described in method 7A-1 the above method of producing 7-A.

The way 8-2

This method is a method of obtaining the compound (I-A) of the present invention from the compound (8b), that is, the above intermediate compound (XII).

(1) If R1or R9not contain a hydroxyl, primary or secondary amino group, and when Y represents a group other than the group represented by the formula-NH-:

Method 1

The compound (8b) can interact with arylisocyanates with obtaining the compound (I-A) of the present invention. In the reaction system can also be added acid, such as camphorsulfonate. As a solvent it is possible to use a mixture of toluene and methanol, a mixture of toluene and ethanol, acetonitrile, N,N-dimethylformamide, tetrahydrofuran and the like, the reaction Temperature is in the range from room temperature to the boiling temperature under reflux. The reaction time ranges from 10 minutes to 30 hours.

Method 2

The compound (8b) can interact with arylisocyanates with obtaining the compound (I-A) of the present invention. The solvent can be used N,N-dimethylformamide, tetrahydrofuran, and so what. The reaction temperature is in the range from 0°C to the boiling temperature under reflux. The reaction time ranges from 10 minutes to 30 hours.

Method 3

The compound (8b) can be subjected to condensation with the compound (3n) to give the compound (I-A) of the present invention. As the condensing means you can use 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride, hexaflurophosphate (1H-1,2,3-benzotriazol-1 iloxi)(three(dimethylamino))phosphonium etc. you can Also use an organic base such as triethylamine. The reaction temperature is in the range from 0°C to the boiling temperature under reflux. The reaction time ranges from 10 minutes to 30 hours.

Method 4

The compound (8b) can interact with N-(chlorocarbonyl)isocyanate or phenylisocyanate and then with an amine to obtain the compound (I-A) of the present invention. You can also use a base, such as Diisopropylamine and triethylamine. The solvent can be used dichloromethane, dichloroethane, tetrahydrofuran and the like, the reaction Temperature is in the range from 0°C to the boiling temperature under reflux. The reaction time ranges from 10 minutes to 30 hours.

Method 5

The compound (8b) can interact with the compound (6b) with images of the of the compound (I-A) of the present invention. The solvent can be used N,N-dimethylformamide, dimethylsulfoxide, N-organic, tetrahydrofuran, etc. can Also be used a base such as sodium hydride, pyridine and triethylamine. The reaction temperature is in the range from 0°C to the boiling temperature under reflux. The reaction time ranges from 10 minutes to 30 hours.

Method 6

If R1, R9or R10not contain alkoxycarbonyl:

The compound (8b) is subjected to condensation with the compound (3k), then remove the protection group, R103the compounds obtained, and then subjected to condensation with the amine or its salt and receive the compound (I-A) of the present invention.

In the condensation reaction of the compound (8b) with compound (3k) as a condensing means you can use 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride, hexaflurophosphate (1H-1,2,3-benzotriazol-1 iloxi)(three(dimethylamino))phosphonium etc. you can Also use a base, such as triethylamine. The solvent can be used tetrahydrofuran, N,N-dimethylformamide and the like, the reaction Temperature is in the range from 0°C to the boiling temperature under reflux. The reaction time ranges from 10 minutes to 30 hours.

Removal of the protecting group R103you can use the hydrolysis of p is outstay grounds, etc.

For condensation with the amine or its salt, you can use the General method of condensation of carboxylic acids with amine. For example, the solvent can be used N,N-dimethylformamide and tetrahydrofuran, as well as condensing means you can use carbonyldiimidazole, dicyclohexylcarbodiimide, the hydrochloride of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide and hexaflurophosphate (1H-1,2,3-benzotriazol-1 iloxi)(three(dimethylamino))phosphonium. You can also use a base, such as triethylamine. The reaction temperature is in the range from 0°C to the boiling temperature under reflux. The reaction time ranges from 10 minutes to 30 hours.

(2) If R1or R9contains a hydroxyl, primary or secondary amino group, or if Y1refers to a group represented by the formula-NH-:

After protection of the above substituents, if necessary, you can perform the above-described reaction with the subsequent removal of the protective groups suitable means and obtaining the compound (I-A) of the present invention.

(3) After completion of the way of a replacement group for R1or R9can be modified by conventional reactions such as oxidation, reduction, complex etherification, amidation, introduction of a protective group, removing the protective groups and hydrolysis, which PR is lead, using appropriate methods, as described in method 7A-1 the above method of producing 7-A.

The way 8-3

This method is a method of oxidizing the compound (I-B) of the present invention to compounds (I-C) of the present invention. As the oxidizing means you can use hydrogen peroxide, peracetic acid, salt metamodel acid, 3-chloroperbenzoic acid and the like as a solvent can be used methanol, water, dichloromethane, chloroform and the like, the reaction Temperature is in the range from 0°C to the boiling temperature under reflux. The reaction time ranges from 10 minutes to 30 hours.

The method of obtaining 9

The method of obtaining the intermediate (1d), where X denotes a group represented by formula-C(R10b)=

This diagram L3denotes chlorine or bromine; X101denotes chlorine, bromine or iodine; R10bdenotes halogen, cyano, C1-6alkyl, C2-6alkenyl, C2-6quinil or a group represented by the formula-CO-R12where R12has the above meaning; R10drepresents C1-6alkyl; R10edenotes hydrogen or C1-4alkyl; R10f, R10gand R10hmay be the same or different and each denotes hydrogen or C1-4Ala is l, provided that the total number of carbon atoms in R10f, R10gand R10his in the range from 0 or more to 4 or less; R10krepresents C1-6alkyl; and the other symbols have the above values.

The way 9-1

This method is a method of chlorination, synthesized or iodination of the compound (9a) on the 5 position of obtaining compound (9b). For example, you can use a halogenation agent, such as iodine, N-iodosuccinimide, bromine, N-bromosuccinimide and N-chlorosuccinimide. The solvent can be used, for example, N,N-dimethylformamide, dimethylsulfoxide, dichloromethane and acetonitrile. The reaction temperature is in the range from 0°C to the boiling temperature under reflux. The reaction time ranges from 10 minutes to 48 hours.

The way 9-2

This method is a method of transformation groups X101compound (9b) a cyano obtaining compound (9c). With regard to the combination of L3and X101when cyanidation, X101preferably represents iodine or bromine, if L3denotes chlorine, and X101preferably represents iodine, if L3denotes bromine. For example, in the presence of a palladium catalyst such as tetrakis(triphenylphosphine)palladium(0) and dichlorobis(triphenylphosphine)palladium(II), using 0.5-0.6 equivalent is in cyanide zinc relative to the compound (9b), or 1.0-1.2 equivalents of potassium cyanide or trimethylsilylacetamide with respect to the compound (9b). The solvent can be used, for example, N,N-dimethylformamide, dioxane or tetrahydrofuran. The reaction temperature ranges from room temperature to the boiling temperature under reflux. The reaction time ranges from 10 minutes to 10 hours.

The way 9-3

This method is a method of obtaining compound (9d) from the compound (9c). You can use the hydrolysis in the presence of inorganic bases such as potassium carbonate and hydrogen peroxide. As a solvent it is possible to use dimethyl sulfoxide and the like, the reaction Temperature is in the range from 0°C to the boiling temperature under reflux. The reaction time ranges from 10 minutes to 10 hours. You can also use the method comprising heating under reflux in a solvent such as toluene and tetrahydrofuran, in the presence of trimethylsilanol potassium, as described in Tetrahedron Lett., 41, 3747(2000). The reaction time ranges from 10 minutes to 60 hours.

The way 9-4

This method is a method of obtaining compound (9e) from the compound (9b). You can use the way you interact with (1-ethoxyphenyl)tributiloltin in the presence of a palladium catalyst, that the CSOs as dichlorobis(triphenylphosphine)palladium(II) and tetrakis(triphenylphosphine)palladium(0). In the reaction system, you can add salt, such as lithium chloride. The solvent can be used tetrahydrofuran, N,N-dimethylformamide, N-the organic and the like, the reaction Temperature is in the range from room temperature to the boiling temperature under reflux. The reaction time ranges from 10 minutes to 60 hours.

In addition to the above-described method, it is possible to mention Tetrahedron, 53 (14), 5159 (1997).

Method 9-5

This method is a method of obtaining compound (9f) from the compound (9b). You can use the mode of interaction of the alcohol represented by the formula, R10d-OH, with carbon monoxide in the presence of a palladium catalyst, such as dichlorobis(triphenylphosphine)palladium(II). In the reaction system, you can add a base, such as triethylamine and diisopropylethylamine. As a solvent, you can use the alcohol represented by the formula, R10a-OH, tetrahydrofuran, N,N-dimethylformamide, N-organic, dimethylsulfoxide and the like, the reaction Temperature is in the range from room temperature to the boiling temperature under reflux. The reaction time ranges from 10 minutes to 60 hours.

In addition to the above-described method, it is possible to mention Tetrahedron Lett., 25 (51), 5939 (1984).

The way 9-6

Yes the tion method is a method for obtaining compounds (9g) from the compound (9b). The compound (9b) can interact with an acetylene derivative in the presence of a palladium catalyst, such as dichlorobis(triphenylphosphine)palladium(II) with a compound (9g). In the reaction system, you can add organic base, such as triethylamine, or an inorganic base such as potassium carbonate and sodium hydroxide. At the same time, there may be a halide monovalent copper. The solvent can be used tetrahydrofuran, N,N-dimethylformamide, N-organic, dioxane, 1,2-dimethoxyethane, toluene, benzene, acetonitrile and the like, the reaction Temperature is in the range from room temperature to the boiling temperature under reflux. The reaction time ranges from 10 minutes to 60 hours.

The way 9-7

This method is a method of obtaining compound (9h) from the compound (9b). The compound (9b) can interact with the derived trialkylsilanes in the presence of a palladium catalyst, such as dichlorobis(triphenylphosphine)palladium(II), to obtain the compounds (9h). In the reaction system, you can add hexamethylphosphoramide, etc. as a solvent can be used tetrahydrofuran, N,N-dimethylformamide, N-organic, dimethylsulfoxide and the like, the reaction Temperature is in the range from room temperature to temperature the tours boiling under reflux. The reaction time ranges from 10 minutes to 60 hours.

In addition to the above-described method, it is possible to mention Tetrahedron, 53 (14), 5159 (1997).

The way 9-8

This method is a method of obtaining compound (9k) from the compound (9b). You can use the way of interaction with carbon monoxide in the presence of a palladium catalyst, such as dichlorobis(triphenylphosphine)palladium(II), and sodium formate as described in Bull. Chem. Soc. Jpn., 67 (8), 2329 (1994). The solvent can be used tetrahydrofuran, N,N-dimethylformamide, N-organic, dimethylsulfoxide and the like, the reaction Temperature is in the range from room temperature to the boiling temperature under reflux. The reaction time ranges from 10 minutes to 60 hours.

The way 9-9

This method is a method of obtaining compound (9m) from the compound (9b). You can use way to interact with the reagent, obtained from halogenoalkane and chloride of zinc(II) in the presence of a palladium catalyst, such as dichlorobis(triphenylphosphine)palladium(II), as described in J. Org. Chem., 2001, 66 (20), 605. The solvent can be used tetrahydrofuran, and the like, the reaction Temperature is in the range from room temperature to the boiling temperature under reflux. The reaction time nah what is in the interval from 10 minutes to 60 hours. Alternative you can use the way you interact with tetraalkyllead in the presence of a palladium catalyst, such as dichlorobis(triphenylphosphine)palladium(II), as described in Tetrahedron Lett. 1996, 37 (14), 2409-2412. The solvent can be used toluene, and the like, the reaction Temperature is in the range from room temperature to the boiling temperature under reflux. The reaction time ranges from 10 minutes to 60 hours.

Reactions similar to those described in methods 9-1-9-9, can be used for the conversion of the substituent in the 5 position (R10) pyridine cycle various intermediate compounds described in the production method of 1 - method of obtaining 8.

"Leaving group" may be any group commonly used in organic synthesis as leaving groups, and not particularly limited. Examples of leaving groups include halogen, for example chlorine, bromine and iodine; a nitro-group; alkylsulfonate, for example, methanesulfonate, tripterocalyx, econsultancy; arylsulfonate, for example, benzosulfimide and p-toluensulfonate; alkanox, for example, acetoxy, triptoreline.

The protective group for the amino group can be any group commonly used in organic synthesis for the protection of amino group, and particularly not limited to the scarfing. Examples of protective groups for amino group include substituted or unsubstituted acyl such as formyl, acetyl, chloroacetyl, dichloroacetyl, propionyl, phenylacetyl, phenoxyacetyl and titilate; alkoxycarbonyl, such as tert-butoxycarbonyl; substituted or unsubstituted, benzyloxycarbonyl, such as benzyloxycarbonyl and 4-nitrobenzenesulfonyl; substituted or unsubstituted alkyl, such as methyl, tert-butyl and 2,2,2-trichloroethyl; substituted benzyl, such as trityl, 4-methoxybenzyl, 4-nitrobenzyl and diphenylmethyl; alkylcarboxylic, such as pivaloyloxymethyl; alkylsilane, such as trimethylsilyl and tert-butyldimethylsilyl; alkylchlorosilanes, such as trimethylsilylmethyl, trimethylsilyloxy, tert-butyldimethylsilyloxy, tert-butyldimethylsilyloxy.

Data protective group can be removed in the traditional way, such as hydrolysis and recovery, depending on the type of the protective group.

The protective group for hydroxyl group can be any group commonly used in organic synthesis for the protection of hydroxyl group, and particularly not limited. Examples of protective groups for the hydroxyl group include alkylsilane, such as trimethylsilyl and tert-butyldimethylsilyl; alkoxymethyl, such as methoxime the silt and 2-methoxyethoxymethyl; tetrahydropyranyl; substituted or unsubstituted benzyl, such as benzyl, 4-methoxybenzyl, 2,4-dimethoxybenzyl, 2-nitrobenzyl, 4-nitrobenzyl, trityl; alkenyl, such as allyl; and acyl such as formyl and acetyl.

Data protective group can be removed in the traditional way, such as hydrolysis and recovery, depending on the type of the protective group.

The protective group for a carboxyl group may be any group commonly used in organic synthesis for the protection of the carboxyl group, and particularly not limited. Examples of protective groups for the carboxyl group include substituted or unsubstituted alkyl, such as methyl, ethyl, ISO-propyl, tert-butyl, 2-iodates and 2,2,2-trichloroethyl; alkoxymethyl, such as methoxymethyl, ethoxymethyl and ISO-butoxymethyl; acyloxymethyl, such as butylacetate and pivaloyloxymethyl; alkoxycarbonylmethyl, such as 1-methoxycarbonylmethyl and 1-ethoxycarbonylmethyl; and substituted or unsubstituted benzyl, such as benzyl, 4-methoxybenzyl, 2-nitrobenzyl and 4-nitrobenzyl.

Data protective group can be removed in the traditional way, such as hydrolysis and recovery, depending on the type of the protective group.

In addition to the above-mentioned protective groups you can use groups described in Greene et al., "Protective Groups in Orgaic Synthesis", 2nd Edition, JOHN WILEY & SONS, INC.

The above-described typical examples of the production method of compound (I) of the present invention. Each of the starting compounds and reagents may be in the form of a salt, hydrate or MES, depending on the source material, solvent, etc. and is not limited to the specific connection, while it does not inhibit the reaction. Solvent used varies depending on the source material, reagent, etc. and is not limited to the specific connection, while it does not inhibit the reaction and can dissolve the starting material to some extent.

The compound (I) of the present invention, in free form can be converted to a salt or hydrate in the traditional way.

The compound (I) of the present invention, in the form of a salt or hydrate, can be converted into the free compound (I) in the traditional way.

The compound (I) of the present invention and the various isomers such as geometrical isomers and optical isomers) of the compound (I) of the present invention can be cleaned and identified with the help of traditional methods of separation, including recrystallization, the method using the diastereomeric salts, enzymatic separation, and various chromatographic methods such as thin layer chromatography, the number of the night chromatography and gas chromatography.

For use as a drug compound (I) of the present invention are usually mixed with a suitable additive. However, the connection of the present invention can be used alone without the addition.

The above-mentioned additives include fillers, binders, lubricants, dezintegriruetsja tools, dyes, taste correctors, emulsifiers, surfactants, aid dissolution, suspendresume tools, isotonic means tabularasa tools, antiseptics, antioxidants, stabilizers, absorption accelerators, etc. If desired, these funds can also be combined appropriately.

The fillers include, for example, lactose, white soft sugar, glucose, corn starch, mannitol, sorbitol, starch, alpha-starch, dextrin, crystalline cellulose, soft silicic anhydride, aluminum silicate, calcium silicate, aluminometasilicate magnesium and phosphate of calcium.

Binders include, for example, polyvinyl alcohol, methylcellulose, ethylcellulose, gum Arabic, tragakant, gelatin, shellac, hypromellose, hydroxypropylcellulose, carboxymethylcellulose sodium, polyvinylpyrrolidone and macrogol.

Dezintegriruetsja means include, for example, a crystal is olosu, agar, gelatin, calcium carbonate, sodium bicarbonate, calcium citrate, dextrin, pectin, hydroxypropylcellulose with a low degree of substitution, carboxymethylcellulose, carboxymethylcellulose calcium, croscarmellose sodium, carboximetilkrahmal and carboximetilkrahmal sodium.

Coloring tools include, for example, colouring agents allowed for use in pharmaceutical products, such as Queen-size iron oxide, yellow Queen-size iron oxide, Carmine, caramel, β-carotene, titanium oxide, talc, Riboflavin sodium phosphate, yellow aluminum lacquer, etc.

The taste correctors include cocoa powder, menthol, aromatic powder, menthol oil, borneol, powdered bark of the cinnamon tree, etc.

Emulsifiers or surfactants include, for example, steartrimonium, sodium lauryl sulfate, lauramidopropyl acid, lecithin, glycerol monostearate, fatty acid esters and sucrose and fatty acid esters and glycerin.

Tools that facilitate the dissolution include, for example, polyethylene glycol, propylene glycol, benzyl benzoate, ethanol, cholesterol, triethanolamine, sodium carbonate, sodium citrate, Polysorbate 80 and nicotinamide.

Suspendresume funds in addition to the above-mentioned surface-active substances include all the I, for example, hydrophilic polymers such as polyvinyl alcohol, polyvinylpyrrolidone, methylcellulose, hydroxymethylcellulose, hydroxyethylcellulose and hydroxypropylcellulose.

Isotonic means include, for example, glucose, sodium chloride, mannitol and sorbitol.

Tabularasa means include, for example, phosphate, acetate, carbonate and citrate buffer solutions.

Antiseptics include, for example, methylparaben, propylparaben, chlorobutanol, benzyl alcohol, finitely alcohol, along with dehydroacetic acid and sorbic acid.

The antioxidants include, for example, sulfite, ascorbic acid and α-tocopherol.

Stabilizers include stabilizers, traditionally used to obtain pharmaceuticals.

The absorption accelerators include tools traditionally used to obtain pharmaceuticals.

The composition may be in a form for oral administration such as tablets, powders, granules, capsules, syrups, lozenges and pharmaceutical forms for inhalation; in a form for topical use, such as suppositories, ointments, eye ointments, adhesive tape, eye drops, nasal drops, ear drops, pastes and lotions; and in a form for injection.

The oral composition can be obtained put the m respective Association of the above additives, if necessary, on its surface may be coated.

The form for external use can be obtained by appropriately combining the above-mentioned additives, including fillers, binders, taste correctors, emulsifiers, surfactants, means, to facilitate dissolution, suspendida funds suspendida agents, isotonic agents, antiseptics, antioxidants, stabilizers and accelerators absorption.

A form for injection can be obtained by appropriately combining the above-mentioned additives, in particular emulsifiers, surfactants, means, to facilitate dissolution, isotonic means sautereau agents, antiseptics, antioxidants, stabilizers and accelerators absorption.

The dose of a compound of the present invention for pharmaceutical applications varies depending on the symptoms and age of the patients, but it usually ranges from 0.1 mg to 10 g (preferably from 1 mg to 2 g) in the case of oral composition, from 0.01 mg to 10 g (preferably, from 0.1 mg to 2 g) in the case of outdoor applications, and from 0.01 mg to 10 g (preferably, from 0.1 mg to 2 g) in the case of molds for injection, and the dose can be administered once or divided into two to four servings per day.

EXAMPLES

The compound of the present invention MoE is but to get for example, the methods described below in the examples of the preparation and examples. However, these examples are for illustration only, and in no way limit the connection of the present invention.

Unless otherwise specified, examples of the preparation and examples as silica gel for purification using YMC SIL-60-400/230W.

Unless otherwise specified, for purification by LC-MS using the following conditions.

Column ODS: column WakopakR Combi ODS or YMC Combi ODS-A

Solvent: solution A (0.1% of triperoxonane acid-water), solution B (0.1% of triperoxonane acid-acetonitrile)

Flow rate: 30 ml/min

Stop time: 10 min

Gradient:

0,00 min A: 99%B: 1%

8,00 min A: 20%, B: 80%

8,20 min (A: 0%, B: 100%

Example obtain 1

a 0.5 M solution fenilizotsianata in hexane

To a suspension of phenylacetamide (1,81 g, a 13.4 mmol) in 1,2-dichloroethane (150 ml) add oxalicacid (3,51 ml, with 40.2 mmol) under nitrogen atmosphere at room temperature, followed by stirring at 110°C during the night. The reaction mixture is cooled to room temperature, concentrated under reduced pressure, add n-hexane (26,8 ml) and then treated with ultrasound. The obtained supernatant (fraction solution yellow) in the future use as specified in the header of the reagent.

Example of getting 2

N-(4-forfinal)malonic sour the s methyl ether

Chlorocarbonate acid methyl ester (5,00 g) dissolved in tetrahydrofuran (100 ml) under nitrogen atmosphere, add triethylamine (5,58 ml) and 4-ftoranila (3,79 ml), cooling in a bath containing ice water, then increase the temperature to room temperature and stirred for 4 hours. The reaction mixture is distributed between ethyl acetate and 1 N. HCl. The organic layer was washed with saturated aqueous sodium bicarbonate, water and saturated saline in this order, dried over anhydrous sodium sulfate, concentrated under reduced pressure and dried in vacuum, obtaining specified in the header connection (8,02 g, quantitatively) in the form of crystals of a pale brown color.

Range1H-NMR (CDCl3) δ (ppm): 3,49 (2H, c), 3,81 (3H, c), 6,99-7,10 (2H, m), 7,50-of 7.55 (2H, m), 9,19 (1H, Sirs).

Example for the preparation of 3

N-(4-Forfinal)malonic acid

N-(4-forfinal)malonic acid methyl ester (8,02 g) dissolved in ethanol (80 ml), add the monohydrate of lithium hydroxide (3,19 g) and stirred for 3 hours and 30 minutes To the reaction mixture add 1 N. HCl (84 ml), then evaporated the ethanol under reduced pressure. The remainder absoluut and extracted with a mixture of ethyl acetate-tetrahydrofuran (1:1). The organic layer is dried over anhydrous sodium sulfate and concentrated under reduced pressure. The obtained residue su is ponderous in a mixture of diethyl ether-hexane (1:1). The solid is filtered off, dried in a stream of air, which is specified in the header connection (7,06 g, 94%) as a powder pale brown color.

Range1H-NMR (CD3OD) δ (ppm): 3.40 in (2H, c), 7,02-7,07 (2H, m), 7,50-7,58 (2H, m).

Example 4

N-(2,4-Differenl)malonic acid methyl ester

Chlorocarbonate acid methyl ester (1,00 g) dissolved in tetrahydrofuran (20 ml) under nitrogen atmosphere, add triethylamine (1,12 ml) and 2,4-diptiranjan (0,82 ml), cooling in a bath containing ice water, then increase the temperature to room temperature and stirred for 3 hours and 40 minutes Then add triethylamine (of 0.56 ml) and 2,4-diptiranjan (0,39 ml) and stirred at room temperature overnight. Add triethylamine (0.25 ml) and 2,4-diptiranjan (0.17 ml), followed by stirring at room temperature for 3 hours. Then add triethylamine (0.25 ml) and 2,4-diptiranjan (0.17 ml), followed by stirring at room temperature for 1 hour and 20 minutes the Reaction mixture is distributed between ethyl acetate and 1 N. HCl. The organic layer was washed with saturated aqueous sodium bicarbonate, water and saturated saline in this order, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting residue is purified column x is matography on silica gel (Fuji Silysia NH, eluent: hexane:ethyl acetate = 1:1). The solvent is evaporated, obtaining a residue which is suspended in a mixture of diethyl ether-hexane (1:1). The solid is filtered off, dried in a stream of air, which is specified in the header connection (1,14 g, 68,4%) as a solid pale purple color.

Range1H-NMR (CDCl3) δ (ppm): of 3.53 (2H, c), 3,83 (3H, c), 6,82-6,94 (2H, m), 8,18-8,29 (1H, m), 9,42 (1H, Sirs).

Example of getting 5

N-(2,4-Differenl)malonic acid

N-(2,4-Differenl)malonic acid methyl ester (1,14 g) dissolved in ethanol (10 ml), add the monohydrate of lithium hydroxide (417 mg) and stirred for 3 hours and 30 minutes To the reaction mixture add 1 N. HCl (20 ml), then evaporated the ethanol under reduced pressure. The remainder absoluut and extracted with a mixture of ethyl acetate-tetrahydrofuran (1:1). The organic layer is dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting residue is suspended in a mixture of diethyl ether-hexane (1:1). The solid is filtered off, dried in the air flow and get listed in the title compound (1.01 g, 94,5%) as a solid pale purple color.

Range1H-NMR (DMSO-d6) δ (ppm): to 3.33 (1H, Sirs), 3,40-of 3.48 (2H, m), 7,02-7,20 (1H, m), 7,28 was 7.45 (1H, m), a 7.85-8,00 (1H, m), 9,98 (1H, c).

An example of obtaining 6

N-(4-Terbisil)of oxalic acid ethyl ester

4-Forbindelsen (1,252 g) dissolved in tetrahydrofuran (30 ml) under nitrogen atmosphere and added dropwise the triethylamine (2.6 ml) and ethylchloride (1,4 ml), cooling in a bath containing ice water, followed by stirring at room temperature for 30 minutes, the Reaction mixture was distributed between ethyl acetate and saturated aqueous sodium bicarbonate. The organic layer is washed with water, 1 N. HCl, water and saturated saline in this order, then dried over anhydrous sodium sulfate. The solvent is evaporated under reduced pressure, obtaining a residue, which is purified column chromatography on silica gel (eluent: hexane:ethyl acetate = 1:1), and receive specified in the header connection (1,851 g, 82%) as white crystals.

Range1H-NMR (CDCl3) δ (ppm): of 1.39 (3H, t, J=7.2 Hz), 4,35 (2H, q, J=7.2 Hz), 4,49 (2H, d, J=6.4 Hz), 7,01-7,07 (2H, m), 7,25-7,30 (2H, m), 7,39 (1H, Shir.).

Example of getting 7

N-(4-Terbisil)oxalic acid

N-(4-Terbisil)oxolamine ethyl ester (1.85 g) was dissolved in methanol (20 ml) - water (5 ml), add the monohydrate of lithium hydroxide (671 mg) and stirred at room temperature for 30 minutes To the reaction mixture add 2 N. HCl (10 ml). The methanol is evaporated under reduced pressure, obtaining a residue that is distributed between ethyl acetate and water. The organic layer p is washed with water and saturated saline in this order, then dried over anhydrous sodium sulfate. The solvent is evaporated under reduced pressure and get the remainder, to which is added a mixture of diethyl ether-hexane to precipitate crystals. The crystals are filtered and dried in a stream of air, getting mentioned in the title compound (1,346 g, 83%) as white crystals.

Range1H-NMR (CDCl3) δ (ppm): 4,51 (2H, d, J=6.0 Hz), 7,00-7,10 (2H, m), 7,20-7,30 (2H, m), EUR 7.57 (1H, Shir.).

Example obtain 8

N-(2-Phenylethyl)of oxalic acid ethyl ester

2-Phenylethylamine (970 mg) was dissolved in tetrahydrofuran (30 ml) under nitrogen atmosphere and dropwise added triethylamine (1,87 ml) and ethylchloride (1.0 ml), cooling in a bath containing ice water, followed by stirring at room temperature for 1 hour. The reaction mixture is distributed between ethyl acetate and saturated aqueous sodium bicarbonate. The organic layer is washed with water, 1 N. HCl, water and saturated saline in this order, then dried over anhydrous sodium sulfate. The solvent is evaporated under reduced pressure, obtaining mentioned in the title compound in crude form (1,83 g) as a yellow oil.

Range1H-NMR (CDCl3) δ (ppm): to 1.38 (3H, t, J=7.2 Hz), is 2.88 (2H, t, J=7.2 Hz), 3,61 (2H, q, J=7.2 Hz), to 4.33 (2H, q, J=7.2 Hz), 7,13 (1H, W), 7,19-to 7.35 (5H, m).

Example of getting 9

N-(2-Phenylethyl)oxalic acid

The crude ethyl ester of N-(2-phenylethyl)oxolamine (1,83 g) dissolved in methanol (20 ml) - water (5 ml) and add monohydrate of lithium hydroxide (671 mg), followed by stirring at room temperature for 1 hour. The methanol is evaporated under reduced pressure, obtaining a residue, to which was added 1 N. HCl (50 ml) and then extracted with ethyl acetate. The organic layer is washed with water and saturated saline, then dried over anhydrous sodium sulfate. The solvent is evaporated under reduced pressure, obtaining a residue which is suspended in a mixture of diethyl ether-hexane (1:5, 60 ml). The solid is filtered off, dried in a stream of air, which is specified in the header connection (1,327 g) as white powder.

Example 10

N-(3-Phenylpropyl)of oxalic acid ethyl ester

3-Phenylpropylamine (1,14 ml) dissolved in tetrahydrofuran (30 ml) under nitrogen atmosphere, was added drop wise addition of triethylamine (1,87 ml) and ethyl chloracetate (1.0 ml), cooling in a bath containing ice water, and stirred at room temperature for 40 minutes, the Reaction mixture was distributed between ethyl acetate and saturated aqueous sodium bicarbonate. The organic layer is washed with water, 1 N. HCl, water and saturated saline in that order, after which the shat over anhydrous sodium sulfate. The solvent is evaporated under reduced pressure, obtaining mentioned in the title compound in crude form from 2.06 g) as a yellow oil.

Range1H-NMR (CDCl3) δ (ppm): of 1.39 (3H, t, J=7.2 Hz), with 1.92 (2H, q, J=7.2 Hz), 2,68 (2H, t, J=7.2 Hz), to 3.38 (2H, q, J=7.2 Hz), 4,34 (2H, q, J=7.2 Hz), 7,10 (1H, W), 7,17-to 7.32 (5H, m).

Example of getting 11

N-(3-Phenylpropyl)oxalic acid

The crude ethyl ester of N-(3-phenylpropyl)oxolamine from 2.06 g) was dissolved in methanol (20 ml) - water (5 ml), add the monohydrate of lithium hydroxide (671 mg) and stirred at room temperature for 1 hour. The methanol is evaporated under reduced pressure, obtaining a residue, to which was added 1 N. HCl (50 ml) and then extracted with ethyl acetate. The organic layer is washed with water and saturated saline in this order, then dried over anhydrous sodium sulfate. The solvent is evaporated under reduced pressure, obtaining a residue which is suspended in a mixture of diethyl ether-hexane (1:5, 60 ml). The solid is filtered off, dried in a stream of air, which is specified in the header connection (1,579 g) as white powder.

Example 12

N-(4-Forfinal)diversiloba acid

Diethyldiphenylurea (196 mg) was dissolved in toluene (2 ml), then add 4-ftoranila (0.1 ml) and heated under reflux overnight. The reactions is nnow the mixture is allowed to cool to room temperature, then add 1 N. HCl (2.5 ml) and extracted with ethyl acetate. The organic layer is dried over anhydrous sodium sulfate, then the solvent is evaporated, getting a brown solid residue. The residue (188 mg) dissolved in a mixture of ethanol (2 ml) - water (0.5 ml), add the monohydrate of lithium hydroxide (42 mg) and stirred for 1 hour. The ethanol is evaporated under reduced pressure and the residue distributed between ethyl acetate and water. To the aqueous layer add 1 N. HCl (1.5 ml)to acidify it, and then extracted with ethyl acetate. The organic layer is dried over anhydrous sodium sulfate, then the solvent is evaporated and dried in vacuum, obtaining the crude N-(4-forfinal)deformationof acid (116 mg) as white powder.

Example of getting 13

N,N-Diethyl-N'-methylpropan-1,3-diamine

To a solution of N,N-diethyl-1,3-propandiamine (10.0 ml) and triethylamine (10.0 ml) in tetrahydrofuran (150 ml) is added dropwise methylchloroform (5,15 ml), cooling in a bath with ice, and stirred at room temperature for 30 minutes To the reaction mixture is added saturated aqueous sodium hydrogen carbonate solution (10 ml), to distribute the mixture. The organic layer is dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue is again dissolved in ethyl acetate (200 ml), dried over potassium carbonate and kontsentriruitesi reduced pressure, receiving a pale yellow oil (8.90 g, ESI-MS (m/z):189). The resulting residue is dissolved in tetrahydrofuran (200 ml), then gradually add the aluminum lithium hydride (2.00 g, 0,826 mmol) under cooling in an ice bath and stirring, followed by stirring under nitrogen atmosphere at room temperature for 15 min and then at 65°C for 1.5 hours. The reaction mixture is cooled in a bath with ice, then add water (2.0 ml), 5 N. aqueous sodium hydroxide solution (2.0 ml) and water (10.0 ml), followed by stirring in an ice bath for 1 hour. Insoluble substances are filtered off, washed with tetrahydrofuran and receive the filtrate, which was concentrated under reduced pressure, obtaining mentioned in the title compound in crude form (9.2 grams, 72,3%) in the form of oil pale yellow color.

Range1H-NMR (CDCl3) δ (ppm): a 1.01 (6H, t, J=7.0 Hz), of 1.65 (2H, m), 2,42 (3H, c), 2,47 (2H, t, J=7.0 Hz), of 2.51 (4H, q, J=7.0 Hz), 2,62 (2H, t, J=7,0 Hz).

ESI-MS (m/z): 145 [M+H]+.

Example of getting 14

Methyl-[3-(4-methylpiperazin-1-yl)propyl]amine

To a solution of 1-(3-aminopropyl)-4-methylpiperazine (1.50 g) in tetrahydrofuran (10 ml), add triethylamine (1,53 ml) and then dropwise methylchloroform (0,811 ml), cooling in a bath with ice, followed by stirring at room temperature for 18 hours. The reaction mixture is distributed between ethyl acetate and feast upon the major aqueous solution of sodium bicarbonate. The organic layer was washed with saturated saline, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The aqueous layer was too concentrated under reduced pressure, obtaining a residue, to which is added tetrahydrofuran (100 ml), and filtered insoluble substances. The filtrate is combined with the previously obtained residue and concentrated under reduced pressure, obtaining the remainder (549 mg). The resulting residue is dissolved in tetrahydrofuran (10 ml), gradually add the aluminum lithium hydride (107 mg) under cooling in a bath with ice and stirring, and then stirred under nitrogen atmosphere at room temperature for 30 min, heated to 65°C and stirred for 2 hours. The reaction mixture is cooled in a bath with ice and then add water (0,11 ml), 5 N. aqueous sodium hydroxide solution (0,11 ml) and water (0,55 ml) in that order, followed by stirring in a bath with ice for 1 hour. The insoluble matter is filtered off and washed with tetrahydrofuran and receive the filtrate, which was concentrated under reduced pressure, obtaining mentioned in the title compound in crude form (1.63 g, 26,3%) as a yellow oil.

ESI-MS (m/z): 172 [M+H]+.

Example get 15

2-Amino-4-(2-fluoro-4-nitrophenoxy)pyridine

2-Amino-4-chloropyridine (8.00 g) was dissolved in N-methylpyrrole the don (65 ml), add 2-fluoro-4-NITROPHENOL (19,55 g) and N,N-diisopropylethylamine (43,36 ml) followed by stirring at 160°C for 41 hours. The reaction mixture is cooled to room temperature and partitioned between a mixture of ethyl acetate-tetrahydrofuran (1:1) and 2 N. aqueous sodium hydroxide solution. The organic layer is washed with water and saturated saline in this order. The aqueous layer was again extracted with ethyl acetate. The combined organic layer is dried over anhydrous sodium sulfate. The solvent is evaporated under reduced pressure, obtaining a residue, which is purified column chromatography on silica gel (eluent: hexane:ethyl acetate = 1:2, then ethyl acetate). The fractions containing the target compound, concentrate, and get the remainder, to which is added ethyl acetate to precipitate crystals. The crystals are filtered, dried in a stream of air, which is specified in the header connection (to 3.02 g, 20%) as crystals milky color.

Range1H-NMR (CDCl3) δ (ppm): to 4.52 (2H, Sirs), equal to 6.05 (1H, d, J=1.6 Hz), 6,30 (1H, DD, J=2,0, 5.6 Hz), 7,20-7,30 (1H, m), 8,02 (1H, d, J=5.6 Hz), 8,05-of 8.15 (2H, m).

Example 16

4-(2-Fluoro-4-nitrophenoxy)-2-[(pyrrolidin-1-yl)carbylamine]pyridine

2-Amino-4-(2-fluoro-4-nitrophenoxy)pyridine (2,71 g) dissolved in tetrahydrofuran (60 ml) under nitrogen atmosphere and then dropwise added triethylamine (2,27 ml) and faniliar RMIT (2,05 ml), cooling in a bath containing ice water, followed by stirring at room temperature for 25 minutes, the Reaction mixture was distributed between ethyl acetate and saturated aqueous sodium bicarbonate. The organic layer was washed with saturated aqueous sodium bicarbonate and saturated saline in this order, then dried over anhydrous sodium sulfate. The solvent is evaporated under reduced pressure, obtaining the crude 4-(2-fluoro-4-nitrophenoxy)-2-(phenoxycarbonylamino)pyridine (5,00 g). The crude product is dissolved in tetrahydrofuran (50 ml), then add pyrrolidine (3,64 ml) at room temperature and stirred for 1 hour. To the reaction mixture is added saturated aqueous solution of ammonium chloride and then extracted with ethyl acetate. The organic layer was washed with saturated aqueous ammonium chloride and saturated saline in this order, then dried over anhydrous sodium sulfate. The solvent is evaporated under reduced pressure, obtaining a residue, which is purified column chromatography on silica gel (eluent: hexane:ethyl acetate = 1:2 to 1:4, then ethyl acetate), and get mentioned in the title compound (2,927 g, 78%) as crystals pale brown color.

Range1H-NMR (CDCl3) δ (ppm): 1,90-2,00 (4H, m), 3,40-3,5 (4H, m)of 6.65 (1H, DD, J=2,4, 5,6 Hz), 7,12 (1H, Sirs), 7,27-7,33 (1H, m), 7,78 (1H, d, J=2.4 Hz), 8.07-a of 8.15 (3H, m).

Example of getting 17

4-(4-Amino-2-pertenece)-2-[(pyrrolidin-1-yl)carbylamine]pyridine

To a solution of 4-(2-fluoro-4-nitrophenoxy)-2-[(pyrrolidin-1-yl)carbylamine]pyridine (2,927 g) in a mixture of ethanol (100 ml) - water (20 ml) is added electrolytic iron powder (3.0 g) and ammonium chloride (6.0 g), then heated under reflux for 1 hour. The reaction mixture is cooled to room temperature, then add a mixture of ethyl acetate-tetrahydrofuran (1:1) and stirred. The insoluble matter is filtered off through celite and washed with ethyl acetate and water. The organic layer of the filtrate was separated, washed with water and saturated saline in this order, then dried over anhydrous sodium sulfate. The solvent is evaporated under reduced pressure, obtaining a residue which is suspended in a mixture of ethyl acetate-hexane. The crystals are filtered, dried in a stream of air, which is specified in the header connection (2,378 g, 89%) as crystals pale brown color.

Range1H-NMR (CDCl3) δ (ppm): 1,90-2,00 (4H, m), 3,30-to 3.50 (4H, m), of 3.73 (2H, c), of 6.45 (1H, DD, J=2,4, 5,6 Hz), 6,50-6,60 (2H, m), of 6.96 (1H, m), 7,03 (1H, Sirs), to 7.67 (1H, d, J=2.4 Hz), 8,00 (1H, d, J=5.6 Hz).

Example of getting 18

4-(4-Amino-2-pertenece)-2-{[4-(pyrrolidin-1-yl)piperidine-1-yl]carbylamine}pyridine/p>

2-Amino-4-(2-fluoro-4-nitrophenoxy)pyridine (187 mg) was dissolved in tetrahydrofuran (4 ml) under nitrogen atmosphere and then added dropwise a triethylamine (of 0.21 ml) and phenylcarbamate (0,188 ml), cooling in a bath with ice, followed by stirring at room temperature for 20 minutes To the reaction mixture is added N,N-dimethylformamide (2 ml) and 4-(pyrrolidin-1-yl)piperidine (609 mg) at room temperature, followed by stirring over night. The reaction mixture is distributed between ethyl acetate and water. The organic layer was washed with saturated saline and dried over anhydrous sodium sulfate. The solvent is evaporated under reduced pressure, obtaining a residue which is dissolved in methanol (10 ml) - tetrahydrofuran (10 ml), add 10% palladium on coal (200 mg) in an atmosphere of nitrogen, then the nitrogen in the system is replaced with hydrogen and stirred overnight. After replacing the nitrogen in the system, the catalyst is filtered off and washed with ethanol. The filtrate is concentrated under reduced pressure and get the remainder, which is purified column chromatography on silica gel (Fuji Silysia NH, eluent: ethyl acetate, then ethyl acetate:methanol = 95:5), receiving specified in the title compound (214 mg, 71%) as colorless crystals.

Range1H-NMR (CDCl3) δ (ppm): 1,40-1,60 (2H, m), 1,70-1,90 (4H, m), 1,90-2,00 (2H, m), 2,19 (1H, m), 2,50-2,60 (4H, m), 2,96 (2H, m), 3,74 (2H, W is RS), a 4.03-4,10 (2H, m), 6,40-6,60 (3H, m), of 6.96 (1H, m), 7.23 percent (1H, Sirs), 7,58 (1H, c), 8,01 (1H, d, J=5.6 Hz).

Example of getting 19

2-[(Dimethylamino)carbylamine]-4-(2-fluoro-4-nitrophenoxy)pyridine

2-Amino-4-(2-fluoro-4-nitrophenoxy)pyridine (249 mg) was dissolved in tetrahydrofuran (5 ml) under nitrogen atmosphere and then added dropwise a triethylamine (of 0.21 ml) and phenylcarbamate (0,19 ml), cooling in a bath containing ice water, followed by stirring at room temperature for 15 minutes To the reaction mixture are added 2M solution of dimethylamine in methanol (4.0 ml) and stirred for 2 days. The solvent is evaporated under reduced pressure, obtaining a residue, which is purified column chromatography on silica gel (eluent: hexane:ethyl acetate = 1:3, then ethyl acetate), obtaining mentioned in the title compound (219 mg, 68%) as crystals pale yellow color.

Range1H-NMR (CDCl3) δ (ppm): 3,03 (6H, c), only 6.64 (1H, DD, J=2,0, 5.6 Hz), 7,30 (2H, m), 7,51 (1H, d, J=5.6 Hz), 8,05-8,16 (3H, m).

Example of getting 20

4-(4-Amino-2-pertenece)-2-[(dimethylamino)carbylamine]pyridine

2-[(Dimethylamino)carbylamine]-4-(2-fluoro-4-nitrophenoxy)pyridine (218 mg) dissolved in a mixture of ethanol (20 ml) - water (5 ml), add electrolytic iron powder (250 mg) and ammonium chloride (500 mg), and then heated under reflux for 1 hour. The reaction mixture is cooled to room temp the atmospheric temperature, then add ethyl acetate-tetrahydrofuran (1:1), followed by stirring. The insoluble matter is filtered off through celite and washed with ethyl acetate and water. The organic layer of the filtrate was separated, washed with water and saturated saline in this order, then dried over anhydrous sodium sulfate. The solvent is evaporated under reduced pressure, obtaining a residue, which is then suspended in a mixture of diethyl ether-hexane. The crystals are filtered, dried in a stream of air, which is specified in the title compound (180 mg, 91%) as crystals pale yellow color.

Range1H-NMR (CDCl3) δ (ppm): to 3.02 (6H, c), of 3.77 (2H, W), 6,40-6,60 (3H, m), of 6.96 (1H, m), 7,20 (1H, Sirs), 7,63 (1H, d, J=2.0 Hz), 8,01 (1H, d, J=5.6 Hz).

Example of getting 21

4-(4-Amino-2-pertenece)-2-[(methylamino)carbylamine]pyridine

2-Amino-4-(2-fluoro-4-nitrophenoxy)pyridine (347 mg) was dissolved in tetrahydrofuran (7.5 ml) under nitrogen atmosphere and then added dropwise a triethylamine (0,314 ml) and phenylcarbamate (0,282 ml), cooling in a bath containing ice water, followed by stirring at room temperature for 10 minutes To the reaction mixture are added 2M solution of methylamine in tetrahydrofuran (7.5 ml) and stirred for 2 days. The reaction mixture is distributed between ethyl acetate and saturated aqueous bicarbonate soda who I am. The organic layer was washed with saturated aqueous sodium bicarbonate and saturated saline in this order, then dried over anhydrous sodium sulfate. The solvent is evaporated under reduced pressure, obtaining the remainder (1028 mg)which is dissolved in a mixture of ethanol (20 ml) - N,N-dimethylformamide (5 ml) - water (5 ml), then add electrolytic iron powder (500 mg) and ammonium chloride (1.0 g) and heated under reflux for 2 hours. The reaction mixture is cooled to room temperature and then the insoluble matter is filtered off through celite and washed with ethyl acetate and water. The organic layer of the filtrate was separated, washed with water and saturated saline in this order, then dried over anhydrous sodium sulfate. The solvent is evaporated under reduced pressure, obtaining a residue, which is purified column chromatography on silica gel (Fuji Silysia NH, eluent: hexane:ethyl acetate = 1:3, then ethyl acetate). The fractions containing the target compound, concentrate, and get the remainder, which is suspended in a mixture of diethyl ether-hexane. The solid is filtered off, dried in a stream of air, which is specified in the header connection (321,7 mg, 78% of the two ways) in the form of a powder pale yellow color.

Range1H-NMR (CDCl3) δ (ppm): 2.91 in (3H, d, J=4.4 Hz) 3,79 (2H, Sirs), 6,16 (1H, m), 6,40-6,60 (3H, m), 6,93 (1H, m), 7,68 (1H, Sirs), of 7.96 (1H, d, J=6.0 Hz), 9,14 (1H, Sirs).

Example of getting 22

2-Amino-4-(4-amino-2-pertenece)pyridine

2-Amino-4-(2-fluoro-4-nitrophenoxy)pyridine (1.246 g) dissolved in a mixture of methanol (20 ml) - tetrahydrofuran (10 ml) and then added 10% palladium on coal (1.0 g) in a nitrogen atmosphere, after which the nitrogen in the system is replaced with hydrogen and stirred for 6 days. After replacing the nitrogen in the system, the catalyst is filtered off and washed with ethanol. The filtrate is concentrated under reduced pressure, obtaining specified in the header connection (1,182 g, quantitative yield) as brown crystals.

Range1H-NMR (CDCl3) δ (ppm): of 3.77 (2H, Sirs), 4,37 (2H, Sirs), of 5.92 (1H, d, J=2.4 Hz), 6,27 (1H, DD, J=2,4, 5,6 Hz), to 6.43 (1H, m), 6,51 (1H, DD, J=2,4, 12.0 Hz), 6,93 (1H, m), to $ 7.91 (1H, d, J=5.6 Hz).

An example of retrieving 23

N-(4-Forfinal)-N'-[4-(2-aminopyridine-4-yloxy)-3-forfinal]malonamic

2-Amino-4-(4-amino-2-pertenece)pyridine (1,14 g) dissolved in N,N-dimethylformamide (20 ml) under nitrogen atmosphere and then at room temperature add N-(4-forfinal)malonic acid (986 mg), triethylamine (0,697 ml) and hexaflurophosphate (1H-1,2,3-benzotriazol-1 iloxi)[three(dimethylamino)]phosphonium (2,21 g), followed by stirring for 23 hours. The reaction mixture was partitioned between a mixture of ethyl acetate-tetrahydrofuran (1:1) and saturated aqueous solution of hydroc is rbonate sodium. The organic layer was washed with saturated aqueous sodium bicarbonate, water and saturated saline in this order, then dried over anhydrous sodium sulfate. The solvent is evaporated under reduced pressure and get the remainder, which is purified column chromatography on silica gel (Fuji Silysia NH, eluent: ethyl acetate, then ethyl acetate:methanol = 95:5), receiving specified in the header connection (937 mg, 47%) as white crystals.

Range1H-NMR (CDCl3) δ (ppm): 3,55 (2H, c), 4,43 (2H, c)5,94 (1H, d, J=2.4 Hz), 6,28 (1H, DD, J=2,0, 5.6 Hz), 7,00-7,30 (4H, m), 7,50-rate of 7.54 (2H, m), 7,72 (1H, DD, J=2,4, 12.0 Hz), 7,94 (1H, d, J=5.6 Hz), 8,54 (1H, Sirs), 9,29 (1H, Sirs).

Example of getting 24

4-(2-Fluoro-4-nitrophenoxy)-2-[(4-hydroxypiperidine-1-yl)carbylamine]pyridine

2-Amino-4-(2-fluoro-4-nitrophenoxy)pyridine (124,6 mg) dissolved in tetrahydrofuran (2.5 ml) under nitrogen atmosphere and then added dropwise a triethylamine (0,105 ml) and phenylcarbamate (0,094 ml), cooling in a bath with ice, followed by stirring at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure, obtaining a residue which is dissolved in N,N-dimethylformamide (1.25 ml), and then at room temperature is added 4-hydroxypiperidine (253 mg), followed by stirring for 2 hours. To the reaction mixture is added saturated aqueous solution of lorida ammonia and then extracted with ethyl acetate. The organic layer was washed with saturated aqueous ammonium chloride and saturated saline in this order, then dried over anhydrous sodium sulfate. The solvent is evaporated under reduced pressure and get the remainder, which is purified column chromatography on silica gel (eluent: hexane:ethyl acetate = 1:2 to 1:4, then ethyl acetate), obtaining mentioned in the title compound (169 mg, 90%) as a powder pale yellow color.

Range1H-NMR (CDCl3) δ (ppm): 1,40-1,70 (2H, m), 1,90 is 1.96 (2H, m), 3,20 to be 3.29 (2H, m), 3,70-of 3.85 (2H, m), of 3.96 (1H, m), only 6.64 (1H, DD, J=2,4, 6,0 Hz), 7,27 was 7.36 (2H, m), of 7.70 (1H, d, J=2.4 Hz), 8,08-to 8.20 (3H, m).

Example get 25

2-Amino-4-{2-fluoro-4-[3-(2-phenylacetyl)touraid]phenoxy}pyridine

2-Phenylacetylene (0,481 ml) dissolved in acetonitrile (30 ml) under nitrogen atmosphere, then adding potassium thiocyanate (707 mg) at 50°C and stirred at the same temperature for 1.5 hours. After evaporation of the acetonitrile under reduced pressure, add toluene (20 ml) and saturated aqueous sodium hydrogen carbonate solution (20 ml) followed by stirring for 25 minutes the Toluene layer (12 ml) are added to a solution of 2-amino-4-(4-amino-2-pertenece)pyridine (400 mg) in ethanol (10 ml) at room temperature, followed by stirring for 1 hour. The reaction mixture was concentrated under reduced pressure, obtaining the remainder, the cat is who purified column chromatography on silica gel (eluent: ethyl acetate). The fractions containing the target compound are concentrated under reduced pressure, obtaining a residue, to which is added diethyl ether (10 ml)to precipitate crystals, and then diluted with hexane (50 ml). The crystals are filtered, dried in a stream of air, which is specified in the title compound (298 mg, 41%) as white crystals.

Range1H-NMR (CDCl3) δ (ppm): 3,75 (2H, c), 4,43 (2H, Sirs), 5,95 (1H, d, J=2.4 Hz), of 6.29 (1H, DD, J=2,4, 5,6 Hz), 7,16 (1H, m), 7,30-7,47 (6H, m), a 7.85 (1H, DD, J=2,4, and 11.6 Hz), 7,95 (1H, d, J=5.6 Hz), 8,51 (1H, Sirs), 12,43 (1H, Sirs).

Example of getting 26

N-(3-Fluoro-4-{2-[(pyrrolidin-1-carbonyl)amino]pyridine-4-yloxy}phenyl)malonic acid benzyl ester

4-(4-Amino-2-pertenece)-2-[(pyrrolidin-1-yl)carbylamine]pyridine (350 mg) was dissolved in N,N-dimethylformamide (4 ml) and then add monobenzoyl ester of malonic acid (51,0 mg), triethylamine (0,463 ml) and hexaflurophosphate (1H-1,2,3-benzotriazol-1 iloxi)[three(dimethylamino)]phosphonium (1.47 g) at 50°C, followed by stirring at the same temperature for 30 minutes the Reaction the mixture is cooled to room temperature and distributed between ethyl acetate and 1 N. aqueous sodium hydroxide solution. The organic layer was washed with saturated aqueous sodium bicarbonate, water and saturated saline in this order, then dried over anhydrous sulfate on the model. The solvent is evaporated under reduced pressure and get the remainder, which is purified column chromatography on silica gel (eluent: hexane:ethyl acetate = 1:2 to 1:4), receiving specified in the header connection (545,7 mg, quantitative yield) as a yellow oil.

Range1H-NMR (CDCl3) δ (ppm): 1,95 (4H, m), 3.43 points (4H, m), 3,52 (2H, c), of 5.24 (2H, c), 6,55 (1H, DD, J=2,4, 6,0 Hz), 7,06-7,26 (3H, m), 7,32-7,46 (5H, m), 7,62 for 7.78 (2H, m), 8,03 (1H, d, J=6.0 Hz), 9,38 (1H, Sirs).

Example of getting 27

N-(3-Fluoro-4-{2-[(pyrrolidin-1-carbonyl)amino]pyridine-4-yloxy}phenyl)malonic acid

N-(3-Fluoro-4-{2-[(pyrrolidin-1-carbonyl)amino]pyridine-4-yloxy}phenyl)malonic acid benzyl ester (546 mg) dissolved in a mixture of tetrahydrofuran (15 ml) - methanol (15 ml) and then added 10% palladium on coal (236 mg) in a nitrogen atmosphere, after which the nitrogen in the system is replaced with hydrogen and stirred for 1 hour. After replacing the nitrogen in the system, the catalyst is filtered off and washed with methanol. The filtrate is concentrated under reduced pressure and dried in vacuum, obtaining specified in the header connection (354,4 mg, 79.3 percent).

Range1H-NMR (DMSO-d6) δ (ppm): 1,80 (4H, m), 3.00 and-of 3.80 (7H, m), 6,60 (1H, DD, J=2,4, 5,6 Hz), 7,28 was 7.45 (2H, m), 7,46 (1H, d, J=2.4 Hz), 7,78 (1H, DD, J=2,4, 13 Hz), 8,10 (1H, DD, J=0,4, 5.6 Hz), 8,69 (1H, Sirs), or 10.6 (1H, Sirs).

Example of getting 28

3-[4-(2-Fluoro-4-nitrophenoxy)pyridine-2-yl]-1-methyl-1-(1-methylpiperidin-4-yl)urea

<> 4-(2-Fluoro-4-nitrophenoxy)pyridin-2-ylamine (200 mg) is dissolved in tetrahydrofuran (8 ml) under nitrogen atmosphere and then added dropwise a triethylamine (0,336 ml) and phenylcarbamate (0,302 ml) at room temperature, followed by stirring for 30 minutes the Reaction mixture was concentrated under reduced pressure, obtaining a residue which is dissolved in N,N-dimethylformamide (5 ml), and then at room temperature add N-methyl-N-(1-methylpiperidin-4-yl)Amin (0,467 ml) followed by stirring for 4 hours. The reaction mixture is distributed between ethyl acetate and saturated aqueous ammonium chloride. The organic layer was washed with saturated aqueous ammonium chloride, water and saturated saline in this order, then dried over anhydrous sodium sulfate. The solvent is evaporated under reduced pressure, obtaining a residue, which is purified column chromatography on silica gel (Fuji Silysia NH, eluent: ethyl acetate). The obtained fractions are concentrated under reduced pressure and dried in vacuum, obtaining mentioned in the title compound (245 mg, 75,5%) as a solid yellow color.

Range1H-NMR (CDCl3) δ (ppm): 1,50-1,70 (2H, m)to 1.79 (2H, m), 2,04 and 2.13 (2H, m)to 2.29 (3H, c), 2,88 are 2.98 (5H, m), 4.09 to 4,22 (1H, m), of 6.66 (1H, DD, J=2,4, 5,6 Hz), 7,26-to 7.35 (1H, m), 7,74 for 7.78 (1H, m), 8,06-8,13 (2H, m), 8,13-8,19 (2H, m).

An example of obtaining 29

3-[4-(4-amine is 2-pertenece)pyridine-2-yl]-1-methyl-1-(1-methylpiperidin-4-yl)urea

3-[4-(2-Fluoro-4-nitrophenoxy)pyridine-2-yl]-1-methyl-1-(1-methylpiperidin-4-yl)urea (243 mg) dissolved in a mixture of tetrahydrofuran (6 ml) - methanol (6 ml) and then added 10% palladium on coal (128 mg) in a nitrogen atmosphere, after which the nitrogen in the reaction system is replaced by hydrogen and stirred for 3 hours. After replacing the nitrogen in the system, the catalyst is filtered off and washed with methanol. The filtrate is concentrated under reduced pressure, obtaining a residue, which is purified column chromatography on silica gel (Fuji Silysia NH, eluent: ethyl acetate) and concentrated under reduced pressure, obtaining mentioned in the title compound (175 mg, 78,0%) in the form of a powder pale yellow color.

Range1H-NMR (CDCl3) δ (ppm): 1,50-1,70 (2H, m), of 1.78 (2H, m), 1,98-to 2.18 (2H, m), 2,20-of 2.38 (3H, m), 2,82-to 3.02 (5H, m in), 3.75 (2H, m), 4,08-4.26 deaths (1H, m), of 6.45 (1H, DD, J=3.2, and an 8.4 Hz), 6,47 of 6.66 (2H, m), 6,97 (1H, m), 7,17 (1H, Sirs), the 7.65 (1H, d, J=2.0 Hz), 8,03 (1H, d, J=5.6 Hz).

ESI-MS (m/z): 374 [M+H]+.

Example 30

1-(3-Diethylaminopropyl)-3-[4-(2-fluoro-4-nitrophenoxy)pyridine-2-yl]-1-metalmachine

To a solution of 4-(2-fluoro-4-nitrophenoxy)pyridine-2-ylamine (300 mg, 1.2 mmol) and triethylamine (0,335 ml, 2.4 mmol) in tetrahydrofuran (30 ml) is added dropwise phenylcarbamate (0,226 ml, 1.8 mmol) under stirring and cooling in a bath with ice, followed by stirring for 0.5 hours. The reaction mixture was concentrated under reduced Yes the tion, receiving the remainder, to which is added N,N-dimethylformamide (6.0 ml) and N,N-diethyl-N'-methyl-1,3-propandiamine (606 mg, 4.2 mmol) followed by stirring at room temperature for 4 hours and 45 minutes To the reaction mixture are added ethyl acetate (150 ml), washed with saturated aqueous sodium bicarbonate and dried over anhydrous sodium sulfate. The solvent is evaporated and get a residue, which was filtered through silica gel (Fuji Silysia NH, hexane:ethyl acetate = 3:1 to 1:1), obtaining mentioned in the title compound (503 mg, 100%) as a yellow oil.

ESI-MS (m/z): 420 [M+H]+.

An example of retrieving 31

1-(3-Diethylaminopropyl)-3-[4-(4-amino-2-pertenece)pyridine-2-yl]-1-metalmachine

To a solution of 1-(3-diethylaminopropyl)-3-[4-(2-fluoro-4-nitrophenoxy)pyridine-2-yl]-1-metalmachine (503 mg, 1.20 mmol) in methanol (40 ml) - tetrahydrofuran (20 ml) is added 10% palladium on coal (200 mg), followed by stirring in an atmosphere of hydrogen at room temperature for 12 hours. The catalyst is filtered off and washed with methanol. The filtrate is concentrated under reduced pressure and get the remainder, which is purified column chromatography on silica gel (Fuji Silysia NH, ethyl acetate, then ethyl acetate:methanol = 10:1), obtaining mentioned in the title compound (467 mg, 85,6%) as a yellow oil.

Range1H-NMR (DMSO-d6) δ (m is.): to 0.97 (6H, t, J=7.2 Hz), 1,68 (2H, m), a 2.36 (2H, m), 2,52 (4H, m), 2,80 (3H, c), 3,29 (2H, m), 5,43 (2H, m), 6,40 (1H, DD, J=2,4, 8,8 Hz), 6,47-6,51 (2H, m)6,94 (1H, DD, J=8,8, 8,8 Hz), 7,29 (1H, d, J=2.4 Hz), 8,02 (1H, d, J=5.6 Hz), was 9.33 (1H, c).

Example of getting 32

1-(3-Diethylaminopropyl)-3-[4-(2-fluoro-4-nitrophenoxy)pyridine-2-yl]urea

To a solution of 4-(2-fluoro-4-nitrophenoxy)pyridine-2-ylamine (400 mg, to 1.61 mmol) and triethylamine (0,455 ml, 3,26 mmol) in tetrahydrofuran (40 ml) added dropwise phenylcarbamate (0,307 ml, 2.45 mmol) under stirring and cooling in a bath with ice, followed by stirring for 0.5 hours. The reaction mixture was concentrated under reduced pressure, obtaining a residue, to which is added N,N-dimethylformamide (20 ml) and N,N-diethyl-1,3-propandiamine (606 mg, 4.2 mmol) followed by stirring at room temperature for 1 hour and 45 minutes To the reaction mixture are added ethyl acetate (150 ml), washed with saturated aqueous sodium bicarbonate and dried over anhydrous sodium sulfate. The solvent is evaporated and get the remainder, which is purified column chromatography on silica gel (Fuji Silysia NH, eluent: hexane:ethyl acetate = 1:2, then ethyl acetate), obtaining mentioned in the title compound (653 mg, 83.8 percent) in the form of oil pale yellow color.

ESI-MS (m/z): 406 [M+H]+.

An example of obtaining 33

1-(3-Diethylaminopropyl)-3-[4-(4-amino-2-pertenece)pyridine-2-yl]urea

To a solution of 1-(3-diethylamino the filing)-3-[4-(2-fluoro-4-nitrophenoxy)pyridine-2-yl]urea (547 mg, 1.35 mmol) in methanol (40 ml) - tetrahydrofuran (20 ml) is added 10% palladium on coal (200 mg), followed by stirring in an atmosphere of hydrogen at room temperature for 12 hours. The catalyst is filtered off and washed with methanol. The filtrate is concentrated under reduced pressure and get the remainder, which is purified column chromatography on silica gel (Fuji Silysia NH, ethyl acetate, then ethyl acetate:methanol = 10:1), obtaining mentioned in the title compound (316 mg, 62,3%) as a yellow oil.

Range1H-NMR (DMSO-d6) δ (ppm): to 0.94 (6H, t, J=7,0 Hz)of 1.53 (2H, m), of 2.38 (2H, m), 2,43 (4H, q, J=7.0 Hz), 3,14 (2H, m), the 5.45 (2H, m), 6,41 (1H, d, J=8,4 Hz), 6,47-of 6.52 (2H, m), at 6.84 (1H, c), to 6.95 (1H, m), 8,01 (1H, d, J=5.6 Hz), 8,11 (1H, m), the remaining 9.08 (1H, c).

An example of retrieving 34

1-[4-(2-Aminopyridine-4-yloxy)-3-forfinal]-3-[(4-forfinal)acetyl]thiourea

4-Forfinal acetate (169 mg, 1.1 mmol) is dissolved in thionyl chloride (651 mg, of 5.48 mmol) followed by stirring at 100°C for 1 hour. The reaction mixture is cooled to room temperature and thionyl chloride evaporated under reduced pressure. The resulting residue is dissolved in acetonitrile (10 ml), add potassium thiocyanate (213 mg, 2,19 mmol) followed by stirring at 50°C for 1 hour. The reaction mixture is cooled to room temperature, add 4-(4-amino-2-pertenece)pyridin-2-ylamine (160 mg, 0,912 mmol) and stirred is at room temperature in the course of 59.5 hours. The reaction mixture was partitioned between water (50 ml) and ethyl acetate (100 ml). The organic layer was washed with saturated saline solution and dried over sodium sulfate. The solvent is evaporated and get the remainder, which is purified column chromatography on silica gel (Fuji Silysia NH, hexane:ethyl acetate = 1:2, ethyl acetate, and then ethyl acetate:methanol = 10:1), obtaining specified in the header connection (to 84.6 mg, 28%) as yellow powder.

ESI-MS (m/z): 415 [M+H]+.

Example of getting 35

4-Methylpiperazin-1-carboxylic acid [4-(2-fluoro-4-nitrophenoxy)pyridine-2-yl]amide

To a solution of 4-(2-fluoro-4-nitrophenoxy)pyridine-2-ylamine (300 mg, 1.2 mmol) and triethylamine (0,335 ml, 2.4 mmol) in tetrahydrofuran (30 ml) added dropwise phenylcarbamate (0,226 ml, 1.8 mmol) under stirring and cooling in a bath with ice, followed by stirring for 1 hour. The reaction mixture was concentrated under reduced pressure, obtaining a residue, to which is added N,N-dimethylformamide (6.0 ml) and 1-methylpiperazine (537 μl, 4,84 mmol) followed by stirring at room temperature for 3 hours. To the reaction mixture are added ethyl acetate (150 ml), washed with saturated aqueous sodium bicarbonate and dried over anhydrous sodium sulfate. The solvent is evaporated and get the remainder, which is purified column chromatography on silica gel (Fui Silysia NH, eluent: hexane:ethyl acetate = 1:2, then ethyl acetate), obtaining mentioned in the title compound (450 mg, 75,3%) in the form of oil pale yellow color.

Range1H-NMR (CDCl3) δ (ppm): 2,31 (3H, c), 2,43 (4H, m), 3,51 (4H, m), 6,62 (1H, DD, J=2.0 a, 6,0 H), 7,26-7,31 (1H, m), of 7.48 (1H, m), of 7.69 (1H, d, J=2.0 Hz), 8,06-8,13 (3H, m).

ESI-MS (m/z): 376 [M+H]+.

Example of getting 36

4-Methylpiperazin-1-carboxylic acid [4-(4-amino-2-pertenece)pyridine-2-yl]amide

To a solution of 4-methylpiperazin-1-carboxylic acid [4-(2-fluoro-4-nitrophenoxy)pyridine-2-yl]amide (339 mg, of 0.903 mmol) in methanol (30 ml) is added 10% palladium on coal (100 mg), followed by stirring in an atmosphere of hydrogen at room temperature for 2 hours. The catalyst is filtered off. The filtrate is concentrated under reduced pressure and get the remainder, which is purified column chromatography on silica gel (Fuji Silysia NH, hexane:ethyl acetate = 1:1, then ethyl acetate), obtaining mentioned in the title compound (196 mg, 62.8%) as a yellow oil.

Range1H-NMR (CDCl3) δ (ppm): 2,30 (3H, c), is 2.41 (4H, m), 3,50 (4H, m), with 3.79 (2H, Sirs), to 6.43 (1H, DDD, J=1,2, 2,4, 8,8 Hz), 6,47-6,51 (2H, m), 6,93 (1H, m), of 7.48 (1H, m), 7,56 (1H, m), 7,98 (1H, d, J=5.6 Hz).

An example of retrieving 37

tert-Butyl 4-[4-(2-fluoro-4-nitrophenoxy)pyridine-2-ylcarbonyl]piperidine-1-carboxylate

To a solution of 4-(2-fluoro-4-nitrophenoxy)pyridine-2-ylamine (400 mg, to 1.61 mmol) in N,N-dimethylformamide (16 ml) we use the t Boc-isonipecotic acid (554 mg, to 2.42 mmol), triethylamine (0,673 ml of 4.83 mmol) and hexaphosphate benzotriazol-1-yloxytris(dimethylamino)phosphonium (1.07 g, 2,42 mmol) followed by stirring at room temperature for 6.5 hours. Add Boc-isonipecotic acid (554 mg, 2,42 mmol), triethylamine (0,673 ml of 4.83 mmol) and hexaphosphate benzotriazol-1-yloxytris(dimethylamino)phosphonium (1.07 g, 2,42 mmol) followed by stirring at room temperature for 3 hours. Add another portion of Boc-isonipecotic acid (554 mg, 2,42 mmol), triethylamine (0,673 ml of 4.83 mmol) and hexaphosphate benzotriazol-1-yloxytris(dimethylamino)phosphonium (1.07 g, 2,42 mmol) followed by stirring at room temperature for 3 days. To the reaction mixture are added ethyl acetate (150 ml), washed with saturated aqueous sodium bicarbonate and dried over anhydrous sodium sulfate. The solvent is evaporated and get the remainder, which is then subjected to column chromatography on silica gel (Fuji Silysia NH, eluent: hexane:ethyl acetate = 1:1, then ethyl acetate), obtaining mentioned in the title compound in crude form (548 mg) as a yellow oil.

ESI-MS (m/z): 461 [M+H]+.

An example of retrieving 38

tert-Butyl 4-[4-(4-amino-2-pertenece)pyridine-2-ylcarbonyl]piperidine-1-carboxylate

To a solution of the crude tert-butyl 4-[4-(2-fluoro-4-nitrophenoxy is)pyridine-2-ylcarbonyl]piperidine-1-carboxylate (548 mg) in methanol (50 ml) is added 10% palladium on coal (100 mg), followed by stirring in an atmosphere of hydrogen at room temperature for 2 hours. The catalyst is filtered off. The filtrate is concentrated under reduced pressure and get the remainder, which is then subjected to column chromatography on silica gel (Fuji Silysia BW-300, eluent: hexane:ethyl acetate = 1:1-1:2, then ethyl acetate)to give a mixture of original substances and target connections. This mixture is again dissolved in methanol (50 ml) and then added 10% palladium on coal (100 mg), followed by stirring in an atmosphere of hydrogen at room temperature for 2 hours. The catalyst is filtered off. The filtrate is concentrated under reduced pressure, obtaining a residue, which is then filtered through silica gel. The filtrate is concentrated under reduced pressure, obtaining mentioned in the title compound (185 mg) as a yellow oil.

Range1H-NMR (CDCl3) δ (ppm): to 1.45 (9H, c), 1,62-of 1.73 (2H, m), 1,82 is 1.86 (2H, m), is 2.37 (1H, m), is 2.74 (2H, m), 4,14 (2H, m), 6,45 (1H, DDD, J=1,4, 2,4, and 8.4 Hz), 6,51 (1H, m), is 6.61 (1H, DD, J=2,4, 6,0 Hz)6,94 (1H, m), 7,26 (1H, d, J=1.2 Hz), 7,88 (1H, Sirs), with 8.05 (1H, d, J=6.0 Hz), 8,67 (1H, Sirs).

An example of retrieving 39

tert-Butyl 4-{4-[2-fluoro-(3-phenylacetylamino)phenoxy]pyridine-2-ylcarbonyl}piperidine-1-carboxylate

To a solution of tert-butyl 4-[4-(4-amino-2-pertenece)pyridine-2-ylcarbonyl]piperidine-1-carboxylate (100 mg, 0,232 mmol) in tetrahydrofuran (4 ml) add 0,5M solution fenilizotsianata in hexane (1.9 ml, of 0.93 mmol, example of getting 1) with subsequent lane is messianism in nitrogen atmosphere at room temperature for 2 hours. The reaction mixture is distributed between ethyl acetate (100 ml) and saturated aqueous sodium hydrogen carbonate (50 ml). The organic layer is dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting residue is purified column chromatography on silica gel (Fuji Silysia NH, eluent: hexane:ethyl acetate = 1:1, ethyl acetate, and then ethyl acetate:methanol = 10:1), obtaining mentioned in the title compound (60 mg, 43.7 per cent) in the form of a yellow oil.

Range1H-NMR (DMSO-d6) δ (ppm): the 1.44 (9H, c), 1,62-of 1.73 (2H, m), of 1.85 (2H, m), is 2.41 (1H, m)of 2.75 (2H, m), 3,76 (2H, c), 4,14 (2H, m), is 6.61 (1H, DD, J=2,4, 6,0 Hz), 7,10-to 7.18 (2H, m), 7,30-7,41 (5H, m), 7,66 (1H, DD, J=2,8, and 11.8 Hz), 7,81 (1H, d, J=2.4 Hz), 8,08 (1H, d, J=6.0 Hz), 8,64 (1H, c), 9,10 (1H, c), 10,71 (1H, c).

Example of getting 40

tert-Butyl 4-(4-{2-fluoro-4-[3-(4-forfinal)acetylthiourea]phenoxy}pyridine-2-ylcarbonyl)piperidine-1-carboxylate

To a solution of 1-[4-(2-aminopyridine-4-yloxy)-3-forfinal]-3-[(4-forfinal)acetyl]thiourea (84,6 mg, 0,204 mmol) in N,N-dimethylformamide (2.0 ml) is added Boc-isonipecotic acid (93,5 mg, 0,408 mmol), triethylamine (0,0853 ml, 0,612 mmol) and hexaphosphate benzotriazol-1-yloxytris(dimethylamino)phosphonium (180 mg, 0,408 mmol) followed by stirring at room temperature for 88 hours. Add Boc-isonipecotic acid (93,5 mg, 0,408 mmol), triethylamine (0,0853 ml, 0,612 mmol) and hexaphosphate benzotriazol-1 eloxite the(dimethylamino)phosphonium (180 mg, 0,408 mmol) followed by stirring at room temperature for a period of 32.5 hours. The reaction mixture is distributed between ethyl acetate (50 ml), tetrahydrofuran (50 ml) and saturated aqueous sodium hydrogen carbonate (50 ml). The organic layer was washed with 1 N. aqueous sodium hydroxide solution (30 ml) and saturated saline solution in this order, then dried over anhydrous sodium sulfate. The solvent is evaporated and get the remainder, which is then subjected to column chromatography on silica gel (Fuji Silysia BW-300; hexane:ethyl acetate = 1:1, then ethyl acetate), obtaining mentioned in the title compound in crude form (548 mg) as a yellow oil.

ESI-MS (m/z): 648 [M+Na]+.

An example of retrieving 41

2-Amino-4-(2-chloro-4-nitrophenoxy)pyridine

2-Amino-4-chloropyridine (to 2.57 g) dissolved in dimethyl sulfoxide (30 ml) and add 2-chloro-4-NITROPHENOL (6,94 g) and N,N-diisopropylethylamine (14 ml) followed by stirring at 160°C for 6 days. The reaction mixture is cooled to room temperature and distributed between ethyl acetate and 1 N. aqueous sodium hydroxide solution. The organic layer was washed with 1 N. aqueous sodium hydroxide solution and saturated saline solution in this order, then dried over anhydrous sodium sulfate. The solvent is evaporated and get the remainder, which is clear to Nochnoi chromatography on silica gel (eluent: hexane:ethyl acetate = 1:2, then ethyl acetate), obtaining mentioned in the title compound (574 mg, 11%) as brown powder.

Range1H-NMR (CDCl3) δ (ppm): a 4.53 (2H, W), 6,04 (1H, d, J=2.4 Hz), 6,30 (1H, DD, J=2,4, 5,6 Hz), 7, 19 (1H, d, J=8,8 Hz), of 8.04 (1H, d, J=5.6 Hz), 8,16 (1H, DD, J=2,4, 8,8 Hz), 8,40 (1H, d, J=2,4 Hz).

An example of retrieving 42

4-(4-Amino-2-chlorophenoxy)-2-[(pyrrolidin-1-yl)carbylamine]pyridine

2-Amino-4-(2-chloro-4-nitrophenoxy)pyridine (574 mg) dissolved in tetrahydrofuran (10 ml) under nitrogen atmosphere and then added dropwise a triethylamine (0,602 ml) and phenylcarbamate (0,542 ml), cooling in a bath with ice, followed by stirring at room temperature for 10 minutes the Reaction mixture is distributed between ethyl acetate and saturated aqueous sodium bicarbonate. The organic layer was washed with saturated aqueous sodium bicarbonate and saturated saline in this order, then dried over anhydrous sodium sulfate. The solvent is evaporated under reduced pressure, obtaining the crude 4-(2-chloro-4-nitrophenoxy)-2-(phenoxycarbonylamino)pyridine (1,272 g). The crude product (637,3 mg) dissolved in tetrahydrofuran (6.5 ml), add pyrrolidine (1,06 ml) at room temperature, followed by stirring for 1 hour and evaporated the solvent under reduced pressure. The resulting residue is dissolved in a mixture of ethanol (20 m the) - water (5 ml), add electrolytic iron powder (500 mg) and ammonium chloride (1 g), then heated under reflux for 1 hour. The reaction mixture is cooled to room temperature and filtered through celite to remove insoluble matter, which was washed with a mixture of ethyl acetate-tetrahydrofuran (1:1) and water. The organic layer of the filtrate was separated, washed with water and saturated saline in this order, then dried over anhydrous sodium sulfate. The solvent is evaporated under reduced pressure and get the remainder, which is purified column chromatography on silica gel (eluent: ethyl acetate), obtaining mentioned in the title compound (227 mg) in the form of a powder pale yellow color.

Range1H-NMR (CDCl3) δ (ppm): 1,90-2,00 (4H, m), 3,40-to 3.50 (4H, m), 3,70 (2H, W), 6,48 (1H, DD, J=2,4, 5,6 Hz), 6,59 (1H, DD, J=2,8, 8,8 Hz), 6,77 (1H, d, J=2,8 Hz), of 6.96 (1H, d, J=8,8 Hz),? 7.04 baby mortality (1H, Sirs), a 7.62 (1H, d, J=2.4 Hz), 8,01 (1H, d, J=5.6 Hz).

An example of retrieving 43

4-(4-Amino-2-chlorophenoxy)-2-[(morpholine-4-yl)carbylamine]pyridine

The crude 4-(2-chloro-4-nitrophenoxy)-2-(phenoxycarbonylamino)pyridine (634,8 mg) dissolved in tetrahydrofuran (6.5 ml), then added morpholine (0,942 ml) at room temperature, followed by stirring overnight and evaporated the solvent under reduced pressure. The resulting residue is dissolved in this mixture is ol (20 ml) - water (5 ml), add electrolytic iron powder (500 mg) and ammonium chloride (1 g), then heated under reflux for 1 hour. The reaction mixture is cooled to room temperature and filtered through celite to remove insoluble matter, which was washed with a mixture of ethyl acetate-tetrahydrofuran (1:1) and water. The organic layer of the filtrate was separated, washed with water and saturated saline in this order, then dried over anhydrous sodium sulfate. The solvent is evaporated and get the remainder, which is purified column chromatography on silica gel (eluent: ethyl acetate, then ethyl acetate:methanol = 95:5), receiving specified in the header of the connection (is 283.3 mg) in the form of a powder pale yellow color.

Range1H-NMR (CDCl3) δ (ppm): 3,40-of 3.80 (10H, m), of 6.49 (1H, DD, J=2.0 a, 6,0 Hz), is 6.61 (1H, DD, J=2,8, 8,8 Hz), 6,79 (1H, d, J=2,8 Hz), 6,95-6,99 (2H, m), 7,55 (1H, Sirs), 8,02 (1H, d, J=6.0 Hz).

An example of retrieving 44

4-Amino-6-(2-chloro-4-nitrophenoxy)pyrimidine

4-Amino-6-chloropyrimidine (648 mg) dissolved in N,N-dimethylformamide (5 ml)is added 2-chloro-4-NITROPHENOL (1,736 g) and N,N-diisopropylethylamine (3,48 ml) followed by stirring at 160°C during the night. The reaction mixture is cooled to room temperature and distributed between ethyl acetate and 1 N. aqueous sodium hydroxide solution. The organic layer was washed with 1 N. water RA is tworoom sodium hydroxide and saturated saline in this order, then dried over anhydrous sodium sulfate. The solvent is evaporated under reduced pressure and get the remainder, to which is added ethyl acetate (10 ml)to precipitate crystals. The crystals are filtered and dried in a stream of air, getting mentioned in the title compound (230 mg, 17%) as crystals pale yellow color.

Range1H-NMR (CDCl3) δ (ppm): 5,00 (2H, W), 6,10 (1H, c), 7,38 (1H, d, J=8,8 Hz), to 8.20 (1H, DD, J=2,8, 8,8 Hz), by 8.22 (1H, c), scored 8.38 (1H, d, J=2,8 Hz).

An example of retrieving 45

4-(4-Amino-2-chlorophenoxy)-6-[(pyrrolidin-1-yl)carbylamine]pyrimidine

4-Amino-6-(2-chloro-4-nitrophenoxy)pyrimidine (230 mg) was dissolved in tetrahydrofuran (5 ml) under nitrogen atmosphere, then added dropwise a triethylamine (0,24 ml) and phenylcarbamate (0,216 ml), cooling in a bath with ice, followed by stirring at room temperature for 1 hour. Add pyrrolidine (0,507 ml) followed by stirring for another 1 hour. The reaction mixture is distributed between ethyl acetate and saturated aqueous ammonium chloride. The organic layer was washed with saturated aqueous ammonium chloride, water, saturated aqueous sodium bicarbonate and saturated saline in this order, then dried over anhydrous sodium sulfate. The solvent is evaporated under reduced pressure, obtaining a residue that solution is ut in a mixture of ethanol (20 ml) - water (5 ml), and then add electrolytic iron powder (400 mg) and ammonium chloride (800 mg), and then heated under reflux for 2 hours. The reaction mixture is cooled to room temperature and filtered through celite to remove insoluble matter, which was washed with a mixture of ethyl acetate-tetrahydrofuran (1:1) and water. The organic layer of the filtrate was separated, washed with water and saturated saline in this order, then dried over anhydrous sodium sulfate. The solvent is evaporated under reduced pressure and get the remainder, which is purified column chromatography on silica gel (eluent: hexane:ethyl acetate = 1:4, then ethyl acetate), obtaining specified in the header connection (145,5 mg, 51%) as white powder.

Range1H-NMR (CDCl3) δ (ppm): 1,90-of 2.05 (4H, m), 3,40-3,55 (4H, m), 3,70 (2H, Sirs), 6,60 (1H, DD, J=2,4, 5,6 Hz), 6,77 (1H, d, J=2.4 Hz), 6,98 (1H, d, J=5.6 Hz), to 7.15 (1H, Sirs), 7,60 (1H, d, J=0.8 Hz), of 8.37 (1H, d, J=0,8 Hz).

An example of retrieving 46

4-(2-Methyl-4-nitrophenoxy)pyridin-2-ylamine

2-Amino-4-chloropyridine (5.0 g), N-organic (40 ml), 2-hydroxy-5-nitrotoluene (11.9 g) and diisopropylethylamine (20,1 g) is placed in the reaction vessel, and then heated and stirred in a nitrogen atmosphere at 150°C for 5 days. The reaction mixture is cooled to room temperature and concentrate under reduced pressure is I. To the obtained residue is added saturated aqueous sodium hydrogen carbonate solution and stirred at room temperature overnight. To the reaction mixture are added tetrahydrofuran (200 ml) and distribute the mixture. The aqueous layer was extracted with diethyl ether (100 ml). The organic layer was washed with saturated saline (100 ml×2), dried over anhydrous sodium sulfate and concentrated under reduced pressure. The precipitated solid is suspended in diethyl ether and filtered. The solid is washed with a mixture of diethyl ether:ethyl acetate = 1:1 and dried in a stream of air, getting mentioned in the title compound (4,36 g, 45.7 percent) in a solid yellow color.

Range1H-NMR (DMSO-d6) δ (ppm): 2,28 (3H, c), of 5.89 (1H, d, J=2.0 Hz), 6,04 (2H, Sirs), to 6.19 (1H, DD, J=2,4, 5,6 Hz), 7.23 percent (1H, d, J=8,8 Hz), 7,87 (1H, d, J=5.6 Hz), 8,14 (1H, d, J=2,8, 8,8 Hz), 8,29 (1H, d, J=2,8 Hz).

ESI-MS (m/z): 246 [M+H]+.

An example of retrieving 47

Morpholine-4-carboxylic acid [4-(2-methyl-4-nitrophenoxy)pyridine-2-yl]amide

To a solution of 4-(2-methyl-4-nitrophenoxy)pyridin-2-ylamine (1,00 g, 4,08 mmol) in tetrahydrofuran (50 ml), add triethylamine (1,14 ml, 8.16 mmol), then added dropwise to phenylcarbamate (0,768 ml) under stirring and cooling in a bath with ice, followed by stirring for 1 hour. Add phenylcarbamate (0,252 ml) under stirring and Oh is Adeney in a bath with ice, followed by stirring for 30 minutes The reaction mixture was concentrated under reduced pressure, obtaining a residue, to which is added N,N-dimethylformamide (18,9 ml) and morpholine (1,42 ml) followed by stirring at room temperature for 5 hours. The reaction mixture was partitioned between a mixture of ethyl acetate:tetrahydrofuran = 1:1 (150 ml) and water (100 ml). The aqueous layer was extracted with a mixture of ethyl acetate:tetrahydrofuran = 1:1. The combined organic layer was washed with saturated saline and dried over anhydrous sodium sulfate. The solvent is evaporated and get the remainder, which is purified column chromatography on silica gel (Fuji Silysia NH, eluent: hexane:ethyl acetate = 2:1 to 1:1, then ethyl acetate). The crude fraction concentrate, receiving the remainder, which is again purified column chromatography on silica gel (eluent: hexane:ethyl acetate = 1:1, ethyl acetate and then ethyl acetate:methanol = 10:1), obtaining mentioned in the title compound (772 mg, 52,8%) as a colourless solid.

Range1H-NMR (DMSO-d6) δ (ppm): to 2.29 (3H, c), is 3.41 (4H, m), of 3.54 (4H, m), to 6.67 (1H, m), 7,27 (1H, d, J=8,8 Hz), the 7.43 (1H, m), 8,15 (1H, d, J=8,8 Hz), to 8.20 (1H, d, J=5.6 Hz), 8,32 (1H, c), 9,38 (1H, c).

Example obtain 48

Morpholine-4-carboxylic acid [4-(4-amino-2-methylphenoxy)pyridine-2-yl]amide

To a solution of morpholine-4-carboxylic acid [4-(2-methyl-4-nitrophenoxy)pyridine-2-yl]amide (775 mg) in ethanol (50 ml) add e the political powder iron (505 mg), ammonium chloride (967 mg) and water (10 ml) followed by stirring at 90°C for 20 minutes the Reaction mixture is cooled to room temperature and filtered to remove insoluble substances, which are then washed with water and N,N-dimethylformamide in the specified order. The filtrate is concentrated under reduced pressure, obtaining a residue, which is then partitioned between a mixture of ethyl acetate:tetrahydrofuran = 1:1 (200 ml) and water (100 ml). The organic layer was washed with saturated saline and dried over anhydrous sodium sulfate. The solvent is evaporated, receiving the remainder, which is then suspended in ethyl acetate (5 ml) and diluted with diethyl ether (30 ml). The solid is filtered and dried in a stream of air, getting mentioned in the title compound (184 mg, 26,1%) as a colorless powder. Uterine fluid concentrate, receiving the remainder, which is suspended in diethyl ether (30 ml). The solid is filtered and dried in air stream, receiving the additional amount specified in the title compound (207 mg, 29.3 per cent) in the form of a powder pale yellow color.

Range1H-NMR (DMSO-d6) δ (ppm): 1,94 (3H, c), to 3.38 (4H, m), of 3.54 (4H, m), 5,01 (2H, m), 6.42 per-6,48 (3H, m), 6,72 (1H, d, J=8,8 Hz), 7.23 percent (1H, c), of 8.04 (1H, d, J=6.0 Hz), 9,13 (1H, c).

An example of retrieving 49

Pyrrolidin-1-carboxylic acid [4-(2-methyl-4-nitrophenoxy)pyridine-2-yl]amide

To a solution of 4-(2-what ethyl-4-nitrophenoxy)pyridine-2-ylamine (1,00 g) in tetrahydrofuran (50 ml), add triethylamine (1,14 ml), then added dropwise phenylcarbamate (0,768 ml) under stirring and cooling in a bath with ice, followed by stirring for 1.5 hours. Add another portion of phenylcarbamate (0,252 ml) under stirring and cooling in a bath with ice, followed by stirring for 0.5 hours. The reaction mixture was concentrated under reduced pressure, obtaining a residue, to which is added N,N-dimethylformamide (20 ml) and pyrrolidine (1,36 ml) followed by stirring at room temperature for 0.5 hours. The reaction mixture is distributed between ethyl acetate (150 ml) and water (100 ml). The organic layer was washed with saturated saline and dried over anhydrous sodium sulfate. The solvent is evaporated and get the remainder, which is purified column chromatography on silica gel (Fuji Silysia NH, eluent: hexane:ethyl acetate = 2:1 to 1:1, then ethyl acetate), obtaining specified in the header connection (988 mg, 70.7 percent) in the form of a solid pale yellow color.

Range1H-NMR (DMSO-d6) δ (ppm): is 1.81 (4H, m)to 2.29 (3H, c), the 3.35 (4H, m), 6,66 (1H, m), 7,27 (1H, d, J=9.0 Hz), 7,53 (1H, c), 8,15 (1H, m), 8,18 (1H, d, J=5.6 Hz), 8,32 (1H, m), 9,31 (1H, c).

Example of getting 50

Pyrrolidin-1-carboxylic acid [4-(4-amino-2-methylphenoxy)pyridine-2-yl]amide

To a solution of pyrrolidin-1-carboxylic acid [4-(2-methyl-4-nitrophenoxy)pyridine-2-yl]amide (775 mg) in ethanol (50 ml) add elektroliticheskoe iron powder (505 mg), ammonium chloride (967 mg) and water (10 ml) followed by stirring at 90°C for 30 minutes, the Reaction mixture was cooled to room temperature and filtered to remove insoluble substances, which are then washed with water and N,N-dimethylformamide in the specified order. The filtrate is concentrated under reduced pressure and get the remainder, which is distributed between ethyl acetate (100 ml) and water (100 ml). The organic layer was washed with saturated saline and dried over anhydrous sodium sulfate. The solvent is evaporated, obtaining a residue, to which is added ethyl acetate (10 ml), then allowed to stand at room temperature. After deposition of solids add diethyl ether (30 ml) and stirred at room temperature for 2 hours. The solid is filtered off and dried in a stream of air, getting mentioned in the title compound (467 mg, 66,2%) in powder form.

Range1H-NMR (DMSO-d6) δ (ppm): 1,80 (4H, m), of 1.94 (3H, c)to 3.34 (4H, m), 5,01 (2H, m), 6.42 per-6,45 (2H, m), of 6.49 (1H, d, J=2.4 Hz), 6,72 (1H, d, J=8,4 Hz), 7,33 (1H, d, J=2.4 Hz), 8,02 (1H, d, J=5.6 Hz), 8,54 (1H, c).

An example of retrieving 51

1-(3-Diethylaminopropyl)-3-[4-(2-methyl-4-nitrophenoxy)pyridine-2-yl]urea

To a solution of 4-(2-methyl-4-nitrophenoxy)pyridine-2-ylamine and triethylamine (500 mg) in tetrahydrofuran (50 ml) is added dropwise phenylcarbamate (0,384 ml, 4,08 mmol) in AC is shivani and cooling in a bath with ice, followed by stirring for 0.5 hours. The reaction mixture was concentrated under reduced pressure, obtaining a residue, to which is added N,N-dimethylformamide (20 ml) and N,N-diethyl-1,3-propandiamine (1,28 ml) followed by stirring at room temperature for 2 hours. The reaction mixture is distributed between ethyl acetate (150 ml) and water (100 ml). The organic layer was washed with saturated saline, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting residue is purified column chromatography on silica gel (Fuji Silysia NH, eluent: hexane:ethyl acetate = 1:1, then ethyl acetate), obtaining mentioned in the title compound (794 mg, 96.9 percent) in the form of oil pale yellow color.

ESI-MS (m/z): 402 [M+H]+.

An example of retrieving 52

1-[4-(4-Amino-2-methylphenoxy)pyridine-2-yl]-3-(3-diethylaminopropyl)urea

To a solution of 1-(3-diethylaminopropyl)-3-[4-(2-methyl-4-nitrophenoxy)pyridine-2-yl]urea (794 mg) in ethanol (50 ml) is added electrolytic iron powder (442 mg), ammonium chloride (847 mg) and water (10 ml) followed by stirring at 90°C for 1 hour. The reaction mixture is cooled to room temperature and filtered to remove insoluble substances. The filtrate is concentrated under reduced pressure, obtaining a residue, to which is added ethyl acetate (100 ml), washed with saturated aqueous sodium bicarbonate and dried n the d anhydrous sodium sulfate. The solvent is evaporated and get the remainder, which is purified column chromatography on silica gel (eluent: hexane:ethyl acetate = 1:1 to 1:2, ethyl acetate and then ethyl acetate:methanol = 20:1 to 10:1), obtaining mentioned in the title compound (110 mg, 15%).

Range1H-NMR (DMSO-d6) δ (ppm): 0,93 (6H, t, J=7.2 Hz), 1,53 (2H, m)of 1.93 (3H, c), of 2.38 (2H, m), 2,43 (4H, q, J=7.2 Hz), of 3.12 (2H, m), of 5.03 (2H, m), to 6.39 (1H, DD, J=2,4, 6,0 Hz), 6,44 (1H, DD, J=2,4, and 8.4 Hz), of 6.49 (1H, d, J=2.4 Hz), 6,72 (2H, m), of 7.97 (1H, d, J=6.0 Hz), by 8.22 (1H, Sirs), 9,04 (1H, c).

ESI-MS (m/z): 372 [M+H]+.

Example of getting 53

1-[4-(4-Amino-3-chlorophenoxy)pyridine-2-yl]-3-atilmotin

2-Amino-4-(4-amino-3-chlorophenoxy)pyridine (707 mg), disclosed in WO 02/32872, dissolved in tetrahydrofuran (15 ml) under nitrogen atmosphere, then added dropwise a triethylamine (0,523 ml) and phenylcarbamate (0,470 ml), cooling in a bath with ice, then with stirring, gradually increase the temperature to room. After 6 hours the reaction mixture is distributed between ethyl acetate and saturated aqueous sodium bicarbonate. The organic layer was washed with saturated aqueous sodium bicarbonate and saturated saline in this order, then dried over anhydrous sodium sulfate. The solvent is evaporated and get the remainder, which is purified column chromatography on silica gel (eluent: hexane:ethyl acetate = 3:2), not receiving the untreated 4-(4-amino-3-chlorophenoxy)-2-phenoxycarbonylamino (920 mg). The crude product is dissolved in N,N-dimethylformamide (9 ml) and then added a 2M solution of ethylamine in tetrahydrofuran (4.5 ml), followed by stirring at room temperature for 23 hours. The reaction mixture is distributed between ethyl acetate and water. The organic layer was washed with saturated saline and dried over anhydrous sodium sulfate. The solvent is evaporated and get the remainder, which is purified column chromatography on silica gel (eluent: hexane:ethyl acetate = 1:2). The fractions containing the target compound, concentrate, and get the remainder, to which is added hexane-ethyl acetate (5:1)to precipitate crystals. The crystals are filtered and dried in a stream of air, getting mentioned in the title compound (298 mg, 32%) as white crystals.

Range1H-NMR (CDCl3) δ (ppm): 1,22 (3H, t, J=7.2 Hz), 3,37 (2H, m), of 4.05 (2H, c), 6,11 (1H, c), of 6.45 (1H, DD, J=2,8, 6,0 Hz), 6,78-6,85 (2H, m), 7,03 (1H, d, J=2,8 Hz), 7,98 (1H, d, J=6.0 Hz), of 9.21 (1H, Sirs).

An example of retrieving 54

4-(4-Amino-3-chlorophenoxy)-2-[(pyrrolidin-1-yl)carbylamine]pyridine

2-Amino-4-(4-amino-3-chlorophenoxy)pyridine (471 mg), disclosed in WO 02/32872, dissolved in tetrahydrofuran (10 ml) under nitrogen atmosphere, then added dropwise a triethylamine (0,348 ml) and phenylcarbamate (0,313 ml), cooling in a bath with ice, and then gradually increased to room temperature and stirred at Uchenie night. To the reaction mixture add pyrrolidine (2 ml), after which stirring is continued for 1 day. The reaction mixture is distributed between ethyl acetate and water. The organic layer was washed with saturated saline and dried over anhydrous sodium sulfate. The solvent is evaporated and get the remainder, which is purified column chromatography on silica gel (eluent: ethyl acetate). The fractions containing the target compound, concentrate, and get the remainder, to which is added hexane-ethyl acetate (5:1)to precipitate crystals. The crystals are filtered and dried in a stream of air, getting mentioned in the title compound (232 mg, 35%) as white crystals.

Range1H-NMR (CDCl3) δ (ppm): 1,90-2,00 (4H, m), 3,40-3,55 (4H, m)4,00 (2H, c), 6,48 (1H, DD, J=2,0, 5.6 Hz), 6,78 (1H, d, J=8,8 Hz)6,86 (1H, DD, J=2,8, 8,8 Hz), 7,01 (1H, Sirs),? 7.04 baby mortality (1H, d, J=2,8 Hz), to 7.67 (1H, d, J=2.0 Hz), 8,01 (1H, d, J=5.6 Hz).

Example of getting 55

1-[4-(4-Amino-3-chlorophenoxy)pyridine-2-yl]-3-determation

2-Amino-4-(4-amino-3-chlorophenoxy)pyridine (236 mg), disclosed in WO 02/32872, dissolved in tetrahydrofuran (10 ml) under nitrogen atmosphere, then added dropwise a triethylamine (of 0.21 ml) and phenylcarbamate (0,188 ml), cooling in a bath with ice, and then gradually increased to room temperature and stirred over night. To the reaction mixture is added N,N-dimethylformamide (2 ml) and N,N-diethylamine (0.5 ml), the donkey which the stirring is continued for 1 day. The reaction mixture is distributed between ethyl acetate and water. The organic layer is washed with water and saturated saline in this order, then dried over anhydrous sodium sulfate. The solvent is evaporated and get the remainder, which is purified column chromatography on silica gel (eluent: hexane:ethyl acetate = 1:3). The fractions containing the target compound, concentrate, and get the remainder, which is suspended in a mixture of diethyl ether-hexane (1:1), then evaporated the solvent. The residue is dried in vacuum, obtaining specified in the header connection (121,5 mg, 36%) as white powder.

Range1H-NMR (CDCl3) δ (ppm): 1,22 (6H, t, J=6.8 Hz), to 3.36 (4H, q, J=6.8 Hz), 4,01 (2H, Sirs), 6,46 (1H, DD, J=2,4, 5,6 Hz), 6,78 (1H, d, J=8,8 Hz), 6,85 (1H, DD, J=2,4, 8,8 Hz),? 7.04 baby mortality (1H, d, J=2.4 Hz), 7,12 (1H, Sirs), 7,66 (1H, d, J=2.4 Hz), 8,01 (1H, d, J=5.6 Hz).

An example of receiving 56

4-(4-Amino-3-chlorophenoxy)-2-[(morpholine-4-yl)carbylamine]pyridine

2-Amino-4-(4-amino-3-chlorophenoxy)pyridine (236 mg), disclosed in WO 02/32872, dissolved in tetrahydrofuran (10 ml) under nitrogen atmosphere, then added dropwise a triethylamine (of 0.21 ml) and phenylcarbamate (0,188 ml), cooling in a bath with ice, and then gradually increased to room temperature and stirred over night. To the reaction mixture is added N,N-dimethylformamide (2 ml) and morpholine (0.5 ml), after which stirring is continued for the of 1 day. The reaction mixture is distributed between ethyl acetate and water. The organic layer was washed with saturated saline and dried over anhydrous sodium sulfate. The solvent is evaporated and get the remainder, which is purified column chromatography on silica gel (eluent: ethyl acetate). The fractions containing the target compound, concentrate, and get the remainder, which is suspended in a mixture of diethyl ether-hexane, after which the solvent evaporated. The residue is dried in vacuum, obtaining mentioned in the title compound (172 mg, 49%) as white powder.

Range1H-NMR (CDCl3) δ (ppm): 3,49-3,51 (4H, m), 3.72 points-of 3.80 (4H, m), was 4.02 (2H, Sirs), of 6.49 (1H, m), 6,79 (1H, DD, J=1,6, 8.0 Hz), 6,86 (1H, m), 7,05 (1H, m), 7,58 (1H, Sirs), 8,00-8,10 (2H, m).

An example of retrieving 57

4-(4-Amino-3-chlorophenoxy)-2-[(4-methylpiperazin-1-yl)carbylamine]pyridine

2-Amino-4-(4-amino-3-chlorophenoxy)pyridine (236 mg), disclosed in WO 02/32872, dissolved in tetrahydrofuran (10 ml) under nitrogen atmosphere, then added dropwise a triethylamine (of 0.21 ml) and phenylcarbamate (0,188 ml), cooling in a bath with ice, followed by stirring at room temperature for 1.5 hours. To the reaction mixture is added N,N-dimethylformamide (2 ml) and 1-methylpiperazine (0,555 ml), after which stirring is continued for 1 day. The reaction mixture is distributed between ethyl acetate and water. The organic layer is washed with asystem saline and dried over anhydrous sodium sulfate. The solvent is evaporated and get the remainder, which is purified column chromatography on silica gel (eluent: ethyl acetate:methanol = 95:5), receiving specified in the title compound (234 mg, 65%) as a powder pale brown color.

Range1H-NMR (CDCl3) δ (ppm): 2,32 (3H, c), 2,35-of 2.50 (4H, m), 3,40-of 3.60 (4H, m), was 4.02 (2H, Sirs), 6,48 (1H, DD, J=2,4, 5,6 Hz), 6,78 (1H, d, J=8,8 Hz)6,86 (1H, DD, J=2,4, 8,8 Hz),? 7.04 baby mortality (1H, d, J=2.4 Hz), 7,26 (1H, m), 7,58 (1H, d, J=2.4 Hz), 8,01 (1H, d, J=5.6 Hz).

An example of retrieving 58

4-(4-Amino-3-chlorophenoxy)-2-{1-[(tert-butoxycarbonyl)piperidine-4-yl]carbylamine}pyridine

2-Amino-4-(4-amino-3-chlorophenoxy)pyridine (471 mg), disclosed in WO 02/32872, dissolved in N,N-dimethylformamide (10 ml) under nitrogen atmosphere, then added at room temperature triethylamine (0,523 ml), 1-(tert-butoxycarbonyl)piperidine-4-carboxylic acid (573 mg) and hexaflurophosphate (1H-1,2,3-benzotriazol-1 iloxi)[three(dimethylamino)]phosphonium (1106 mg), followed by stirring for 2.5 hours. Add a couple of triethylamine (0,523 ml), 1-(tert-butoxycarbonyl)piperidine-4-carboxylic acid (573 mg) and hexaflurophosphate (1H-1,2,3-benzotriazol-1 iloxi)[three(dimethylamino)]phosphonium (1106 mg), followed by stirring overnight. The reaction mixture is distributed between ethyl acetate and water. The organic layer was washed with saturated aqueous sodium hydrogen carbonate and saturated saline solution specified in the om order then dried over anhydrous sodium sulfate. The solvent is evaporated and get the remainder, which is purified column chromatography on silica gel (eluent: ethyl acetate:hexane = 2:1), receiving the remainder. To the residue is added diethyl ether-hexane to precipitate crystals. The crystals are filtered and dried in a stream of air, getting mentioned in the title compound (644 mg, 72%) as white crystals.

Range1H-NMR (CDCl3) δ (ppm): of 1.46 (9H, c), 1,60-1,80 (2H, m), 1,80-2,00 (2H, m), is 2.37 (1H, m), 2,60-2,90 (2H, m), a 4.03 (2H, Sirs), 4,10-4,30 (2H, m), 6,56 (1H, DD, J=2,4, 5,6 Hz), 6,79 (1H, d, J=8,8 Hz), 6,85 (1H, DD, J=2,4, 8,8 Hz),? 7.04 baby mortality (1H, d, J=2.4 Hz), 7,76 (1H, m), 7,92 (1H, Sirs), 8,07 (1H, d, J=5.6 Hz).

Example retrieve 59

4-{3-Chloro-4-[3-(2-phenylacetyl)touraid]phenoxy}-2-{[1-(tert-butoxycarbonyl)piperidine-4-yl]carbylamine}pyridine

To 4-(4-amino-3-chlorophenoxy)-2-{1-[(tert-butoxycarbonyl)piperidine-4-yl]carbylamine}pyridine (447 mg) add a 0,11M solution phenylacetonitrile in acetonitrile (47 ml) at room temperature, followed by stirring overnight. Insoluble substances are removed by filtration, the filtrate is concentrated under reduced pressure, obtaining a residue, which is purified column chromatography on silica gel (eluent: ethyl acetate:hexane = 1:1). The resulting residue is dried in vacuum, obtaining mentioned in the title compound (527 mg) in the form of a powder pale is altago color.

Range1H-NMR (CDCl3) δ (ppm): of 1.46 (9H, c), 1,60-1,80 (2H, m), 1,80-2,00 (2H, m), is 2.40 (1H, m), 2,60-2,90 (2H, m), of 3.77 (2H, c), 4,00-4,30 (2H, m), 6,23 (1H, m),? 7.04 baby mortality (1H, m), 7,20 is 7.50 (6H, m), 7,87 (1H, m), 8,07 (1H, Sirs), 8,13 (1H, m), scored 8.38 (1H, d, J=8,8 Hz), 8,61 (1H, Sirs), 12,45 (1H, c).

Example of getting 60

4-(4-Amino-3-chlorophenoxy)-2-(ethoxycarbonyl)pyridine

2-Amino-4-(4-amino-3-chlorophenoxy)pyridine (KZT 235.7 mg), disclosed in WO 02/32872, dissolved in tetrahydrofuran (10 ml) under nitrogen atmosphere, then added dropwise a triethylamine (of 0.21 ml) and ethylchloride (0,143 ml), cooling in a bath with ice, followed by stirring at room temperature for 9 hours. The reaction mixture is distributed between ethyl acetate and saturated aqueous sodium bicarbonate. The organic layer was washed with saturated saline and dried over anhydrous sodium sulfate. The solvent is evaporated and get the remainder, which is purified column chromatography on silica gel (eluent: ethyl acetate:hexane = 1:1)to give 4-(4-amino-3-chlorophenoxy)-2-(basetexture)aminopyridine (190 mg, 50%) as a colourless oil. 4-(4-Amino-3-chlorophenoxy)-2-(basetexture)aminopyridine (190 mg) was dissolved in ethanol (5 ml), then add 1 N. aqueous sodium hydroxide solution (1.0 ml) at room temperature, followed by stirring for 15 minutes the Reaction mixture is distributed between ethyl acetate and water. Organizes the second layer was washed with saturated saline and dried over anhydrous sodium sulfate. The solvent is evaporated under reduced pressure, obtaining a residue, to which is added a mixture of diethyl ether-hexane (1:2)to precipitate crystals. The crystals are filtered and dried in a stream of air, getting mentioned in the title compound (121 mg, 79%) as crystals pale brown color.

Range1H-NMR (CDCl3) δ (ppm): of 1.30 (3H, t, J=7.2 Hz), a 4.03 (2H, Sirs), is 4.21 (2H, q, J=7.2 Hz), 6,50 (1H, DD, J=2,4, 5,6 Hz), 6,79 (1H, d, J=8,8 Hz)6,86 (1H, DD, J=2,4, 8,8 Hz), 7,05 (1H, d, J=2.4 Hz), 7,53 (1H, Sirs), 8,09 (1H, d, J=5.6 Hz), 8,18 (1H, Sirs).

An example of retrieving 61

1-[4-(4-Amino-3-chlorophenoxy)pyridine-2-yl]-3-cyclopropylamino

Specified in the title compound obtained as powder pale brown (146 mg, 46%) according to the method of example 53 get from 2-amino-4-(4-amino-3-chlorophenoxy)pyridine (236 mg), disclosed in WO 02/32872, and cyclopropylamine.

Range1H-NMR (CDCl3) δ (ppm): 0,40-0,60 (2H, m), 0,70-0,80 (2H, m), 2,71 (1H, m), of 4.05 (2H, Sirs), 6,46 (1H, DD, J=2,4, 5,6 Hz), 6,70-to 7.00 (4H, m), 7,03 (1H, d, J=2.4 Hz), 7,20-of 7.25 (1H, m), of 7.96 (1H, d, J=5.6 Hz).

An example of retrieving 62

1-[4-(4-Amino-3-chlorophenoxy)pyridine-2-yl]-3-[2-(N,N-diethylamino)ethyl]urea

Specified in the title compound obtained as a colorless oil (154,7 mg, 41%) according to the method of example 53 get from 2-amino-4-(4-amino-3-chlorophenoxy)pyridine (236 mg), disclosed in WO 02/32872, and 2-(N,N-diethylamino)ethylamine.

Range1H-NMR (CDCl3) δ (ppm): was 1.04 (6H, t, J=64 Hz), of 2.58 (4H, q, J=6,4 Hz)of 2.64 (2H, m), 3,42 (2H, m), 4,07 (2H, Sirs), to 6.43 (1H, m), 6,70-of 7.25 (5H, m), of 7.97 (1H, d, J=5.6 Hz), was 9.33 (1H, Sirs).

An example of retrieving 63

4-(4-Amino-3-chlorophenoxy)-2-[4-(pyrrolidin-1-yl)piperidine-1-ylcarbonyl]pyridine

Specified in the header connection receive in the form of a white powder (137,8 mg, 33%) by the method of example 53 get from 2-amino-4-(4-amino-3-chlorophenoxy)pyridine (236 mg), disclosed in WO 02/32872, and 4-(pyrrolidin-1-yl)piperidine.

Range1H-NMR (CDCl3) δ (ppm): 1,20-1,30 (2H, m), 1,40-1,60 (2H, m), 1,70-1,80 (4H, m), 1,90-2,00 (2H, m), of 2.21 (1H, m), 2,50-2,70 (4H, m), of 2.97 (2H, m)to 4.01 (2H, Sirs), 6,47 (1H, DD, J=2,4, 5,6 Hz), 6,78 (1H, d, J=8,8 Hz), 6,85 (1H, DD, J=2,4, 8,8 Hz),? 7.04 baby mortality (1H, d, J=2.4 Hz), EUR 7.57 (1H, d, J=2.4 Hz), 8,00 (1H, d, J=8,8 Hz).

Example of getting 64

4-(4-{3-Chloro-4-[2-(4-tortenelmebol)acetylamino]phenoxy}pyridine-2-ylcarbonyl)piperidine-1-carboxylic acid tert-butyl methyl ether

4-(4-Amino-3-chlorophenoxy)-2-{1-[(tert-butoxycarbonyl)piperidine-4-yl]carbylamine}pyridine (196 mg) was dissolved in N,N-dimethylformamide (2 ml) in nitrogen atmosphere, then add N-(4-forfinal)malonic acid (260 mg), triethylamine (0,184 ml) and hexaflurophosphate (1H-1,2,3-benzotriazol-1 iloxi)[three(dimethylamino)]phosphonium (584 mg) at 50°C, followed by stirring for 1 hour. The reaction mixture is cooled to room temperature and distributed between ethyl acetate and 1 N. aqueous solution of sodium hydroxide. The organic layer industry is saturated with an aqueous solution of sodium bicarbonate, water and saturated saline in this order, then dried over anhydrous sodium sulfate. The solvent is evaporated and get the remainder, which is purified column chromatography on silica gel (Fuji Silysia NH, eluent: hexane:ethyl acetate = 1:3, then ethyl acetate). The fractions containing the target compound, concentrate, and get the remainder, which is dried in vacuum and get listed in the title compound (234,1 mg, up 85.2%) as a colourless oil.

Range1H-NMR (CDCl3) δ (ppm): of 1.39 (9H, c), 1,55-1,70 (2H, m), 1,75-of 1.85 (2H, m), 2,35-of 2.50 (1H, m), 2,60-of 2.75 (2H, m), 3,62 (2H, m), 4,07 (2H, m), 6,55 (1H, DD, J=2,4, 5,6 Hz), 6,85-6,98 (3H, m), 7,10 (1H, m), 7,43-7,52 (2H, m), 7,78 (1H, m), with 8.05 (1H, d, J=5.6 Hz), 8,23 (1H, d, J=8,8 Hz), 9,18 (1H, Sirs), 9,67 (1H, c), 9,92 (1H, c).

Example getting 65

Pyrrolidin-1-thiocarbonic acid [4-(4-amino-3-chlorophenoxy)pyridine-2-yl]amide

2-Amino-4-(4-amino-3-chlorophenoxy)pyridine (250 mg), disclosed in WO 02/32872, dissolved in tetrahydrofuran (5 ml) under nitrogen atmosphere, then added dropwise a triethylamine (0,185 ml) and familiartity (0,184 ml), cooling in a bath with ice, followed by stirring at room temperature for 2.5 hours. To the reaction mixture to add more triethylamine (0,074 ml) and familiartity (0,073 ml) followed by stirring at room temperature for 40 minutes To the reaction mixture add pyrrolidine (0,530 ml) with subsequent mixing of the night. Add another portion of pyrrolidine (0,530 ml) followed by stirring for 1 hour. The reaction mixture is heated to 40°C and stirred for 30 min, then heated to 50°C and stirred for 2.5 hours. The reaction mixture is distributed between ethyl acetate and water. The organic layer was washed with saturated saline and dried over anhydrous sodium sulfate. The solvent is evaporated and get the remainder, which is purified column chromatography on silica gel (eluent: hexane:ethyl acetate = 1:1 to 1:3). The fractions containing the target compound, concentrate, and get the remainder, which is dried in vacuum, obtaining specified in the header of the connection (and 73.2 mg, 19,8%) as a colourless solid.

Range1H-NMR (CDCl3) δ (ppm): 1,80-of 2.30 (4H, m), 3,62 (2H, m), a-3.84 (2H, m), was 4.02 (2H, m), 6,14 (1H, m), to 6.80 (1H, d, J=8,8 Hz), make 6.90 (1H, DD, J=2,8, 8,8 Hz), to 7.09 (1H, d, J=2,8 Hz), to 7.67 (1H, m), of 8.04 (1H, m), 8,23 (1H, m).

An example of retrieving 66

1-[4-(4-Amino-3-chlorophenoxy)pyridine-2-yl]-3-(3-morpholine-4-ylpropyl)urea

4-(4-Amino-3-chlorophenoxy)pyridin-2-ylamine (750 mg, 3,18 mmol) dissolved in tetrahydrofuran (30 ml) and add triethylamine (0,444 ml, 4.77 mmol). Add dropwise phenylcarbamate (0,399 ml, 4.77 mmol) while cooling on ice, followed by stirring at room temperature for 4 hours and 45 minutes Add another portion of triethylamine (0,222 ml) and finish is orformula (0,200 ml) while cooling on ice, followed by stirring for 40 minutes Add another portion of triethylamine (0,111 ml) and phenylcarbamate (0.100 ml) followed by stirring for 40 minutes, the Reaction mixture was concentrated under reduced pressure, obtaining a residue, to which is added N,N-dimethylformamide (10 ml) and 3-(morpholine-4-yl)Propylamine (2,32 ml, 15.9 mmol), followed by stirring at room temperature for 2 hours. The reaction mixture is distributed between ethyl acetate (50 ml) and water (20 ml). The organic layer was washed with saturated aqueous sodium bicarbonate and dried over anhydrous sodium sulfate. The solvent is evaporated, obtaining a solid substance, which is then suspended in ethyl acetate, filtered, washed with ethyl acetate and dried in the air flow, getting mentioned in the title compound (359 mg, services, 0.844 mmol, 27.8 percent) as a colorless powder.

Range1H-NMR (DMSO-d6) δ (ppm): 1,59 (2H, m), 2,28 (2H, m), 2,32 (4H, m)and 3.15 (2H, DD, J=6,4, 6.4 Hz), of 3.56 (4H, t, J=4.4 Hz), are 5.36 of 5.39 (2H, m), 6,47 (1H, DD, J=2,4, 5,6 Hz), PC 6.82-6.89 in (3H, m), was 7.08 (1H, d, J=2.4 Hz), 8,02 (1H, d, J=5.6 Hz), 8,11 (1H, Sirs), 9,06 (1H, c).

ESI-MS (m/z): 406 [M+H]+.

An example of retrieving 67

1-[4-(4-Amino-3-chlorophenoxy)pyridine-2-yl]-3-[3-(1-methylpiperazin-4-yl)propyl]urea

4-(4-Amino-3-chlorophenoxy)pyridin-2-ylamine (750 mg, 3,18 mmol) dissolved in tetrahydrofuran (30 ml) and add triethylamine (0,444 ml, 4.77 mmol). Add dropwise phenylcarbamate (0,399 ml, 4,77 m is ol) under cooling on ice, followed by stirring at room temperature for 4 hours and 45 minutes Add a couple of triethylamine (0,222 ml) and phenylcarbamate (0,200 ml) followed by stirring for 40 minutes, Add another portion of triethylamine (0,111 ml) and phenylcarbamate (0.100 ml) followed by stirring for 40 minutes, the Reaction mixture was concentrated under reduced pressure, obtaining a residue, to which is added N,N-dimethylformamide (10 ml) and 3-(1-methylpiperazin-4-yl)Propylamine (2,32 ml, 15.9 mmol), followed by stirring at room temperature for 2 hours. The reaction mixture is distributed between ethyl acetate (50 ml) and water (20 ml). The organic layer was washed with saturated aqueous sodium bicarbonate and dried over anhydrous sodium sulfate. The solvent is evaporated and get the remainder, which is purified column chromatography on silica gel (Fuji Silysia NH, ethyl acetate, then ethyl acetate:methanol = 10:1 to 20:3). Roughly purified fraction concentrate and again purified column chromatography on silica gel (Fuji Silysia NH, hexane:ethyl acetate = 1:1, ethyl acetate, then ethyl acetate:methanol = 10:1 to 20:3, getting mentioned in the title compound (691 mg, of 1.65 mmol, 51.9 percent) as a colorless powder.

Range1H-NMR (DMSO-d6) δ (ppm): 1.57 in (2H, m)to 2.13 (3H, c), 2,24-2,45 (10H, m), of 3.13 (2H, m), 5,38 (2H, m), 6,47 (1H, DD, J=2,4, 6,0 Hz), 6,82-6,91 (3H, m), was 7.08 (1H, d, J=2.4 Hz), 8,01 (1H, d, J=6.0 Hz), 8,11 (1H, d, J=6,0 Hz), 9,04 (1H, c).

Example of getting 68

Piperidine-karbonovoi acid [4-(4-amino-3-chlorophenoxy)pyridine-2-yl]amide

4-(4-Amino-3-chlorophenoxy)pyridin-2-ylamine (750 mg, 3,18 mmol) dissolved in tetrahydrofuran (30 ml) and add triethylamine (0,444 ml, 4.77 mmol). While cooling on ice is added dropwise phenylcarbamate (0,399 ml, 4.77 mmol), followed by stirring at room temperature for 3.5 hours. Add a couple of triethylamine (0,444 ml) and phenylcarbamate (0,399 ml) while cooling on ice, followed by stirring for 15 minutes Then add N,N-dimethylformamide (6.0 ml) and piperidine (1.5 ml) followed by stirring at room temperature for 5.5 hours. The reaction mixture was concentrated under reduced pressure, add N,N-dimethylformamide (4.0 ml) and piperidine (1.0 ml) followed by stirring at room temperature for 36 hours. The reaction mixture is distributed between ethyl acetate and water. The organic layer was washed with saturated saline and dried over anhydrous sodium sulfate. The solvent is evaporated and get the remainder, which is purified column chromatography on silica gel (eluent: hexane:ethyl acetate = 1:1 to 1:2, ethyl acetate, then ethyl acetate:methanol = 10:1). The fractions containing the target compound, concentrate, and get a solid substance that is suspended in diethyl ether, filtered and dried in a stream of air, getting mentioned in the title compound (462 mg, of 1.33 mmol, 41.9 per cent) in the form t is ejogo substances pale yellow color.

Range1H-NMR (DMSO-d6) δ (ppm): the 1.44 (4H, m), and 1.54 (2H, m)to 3.38 (4H, m), lower than the 5.37 (2H, c), of 6.49 (1H, DD, J=2,2, 5.6 Hz), 6,86-6,89 (2H, m), 7,07 (1H, d, J=2.0 Hz), 7,31 (1H, d, J=2.2 Hz), of 8.06 (1H, d, J=5.6 Hz), 9,05 (1H, c).

ESI-MS (m/z): 347 [M+H]+.

Example of getting 69

Azetidin-1-carboxylic acid [4-(4-amino-3-chlorophenoxy)pyridine-2-yl]amide

4-(4-Amino-3-chlorophenoxy)pyridin-2-ylamine (750 mg, 3,18 mmol) dissolved in tetrahydrofuran (30 ml) and add triethylamine (0,444 ml, 4.77 mmol). Add dropwise phenylcarbamate (0,399 ml, 4.77 mmol) while cooling on ice, followed by stirring at room temperature for 5 hours. Add a couple of triethylamine (0,222 ml) and phenylcarbamate (0,200 ml) while cooling on ice and stirred for 40 minutes Add another portion of triethylamine (0,111 ml) and phenylcarbamate (0.100 ml) while cooling on ice, followed by stirring for 30 minutes the Reaction mixture was concentrated under reduced pressure, obtaining a residue, to which is added N,N-dimethylformamide (10 ml), hydrochloride of azetidine (1,49 g, 15.9 mmol) and triethylamine (2.66 ml of 19.1 mmol) followed by stirring at room temperature for 3 hours. To the reaction mixture are added ethyl acetate (50 ml) and water (20 ml), then add saturated aqueous solution of sodium bicarbonate and distribute the mixture. The organic layer was washed with saturated saline and dried over b is wodnym sodium sulfate. The solvent is evaporated and get the remainder, which is purified column chromatography on silica gel (hexane:ethyl acetate = 1:1, ethyl acetate, then ethyl acetate:methanol = 20:1 to 10:1). The fractions containing the target compound, concentrate, and get a solid substance that is suspended in diethyl ether, filtered and dried in a stream of air, getting mentioned in the title compound (492 mg, 1.54 mmol, 48.5 percent) as a colorless powder.

Range1H-NMR (DMSO-d6) δ (ppm): 2,12 (2H, m), 3,93 (4H, t, J=7.8 Hz), lower than the 5.37 (2H, m), 6,50 (1H, DD, J=2,4, 5.8 Hz), 6,83-6,89 (2H, m), 7,07 (1H, d, J=2.4 Hz), 7,42 (1H, d, J=2.4 Hz), with 8.05 (1H, d, J=5.8 Hz), 8,99 (1H, c).

ESI-MS (m/z): 318 [M+H]+.

Example of getting 70

1-[4-(4-Amino-3-chlorophenoxy)pyridine-2-yl]-3-(3-diethylaminopropyl)urea

4-(4-Amino-3-chlorophenoxy)pyridin-2-ylamine (750 mg, 3,18 mmol) dissolved in tetrahydrofuran (30 ml) and add triethylamine (0,444 ml, 4.77 mmol). While cooling on ice is added dropwise phenylcarbamate (0,399 ml, 4.77 mmol), followed by stirring at room temperature for 5 hours. Add another portion of triethylamine (0,222 ml) and phenylcarbamate (0,200 ml) followed by stirring for 40 minutes, Add another portion of triethylamine (0,111 ml) and phenylcarbamate (0.100 ml) followed by stirring for 30 minutes the Reaction mixture was concentrated under reduced pressure, obtaining a residue,to which is added N,N-dimethylformamide (10 ml) and 3-(diethylamino)Propylamine (2,49 ml, 15.9 mmol) followed by stirring at room temperature for 3 hours. To the reaction mixture are added ethyl acetate (50 ml) and water (20 ml), then add saturated aqueous solution of sodium bicarbonate and distribute the mixture. The organic layer was washed with saturated saline and dried over anhydrous sodium sulfate. The solvent is evaporated and get the remainder, which is then dried in vacuum, obtaining mentioned in the title compound (645 mg, of 1.65 mmol, 51,8%) as a solid pale yellow color.

Range1H-NMR (DMSO-d6) δ (ppm): 0,93 (6H, t, J=7.2 Hz), 1,53 (2H, m), of 2.38 (2H, t, J=7.2 Hz), 2,43 (4H, q, J=7.2 Hz), 3,14 (2H, m), of 5.39 (2H, c), 6,47 (1H, DD, J=2,2, 6,0 Hz), to 6.80 (1H, d, J=2.2 Hz), 6,84-6,89 (2H, m)that was 7.08 (1H, d, J=2.2 Hz), 8,00 (1H, d, J=6.0 Hz), 8,19 (1H, Sirs), 9,07 (1H, c).

Example of getting 71

4-(3-Methyl-4-nitrophenoxy)pyridin-2-ylamine

To a solution of 2-amino-4-chloropyridine (2.50 g, and 19.4 mmol) in N-organic (20 ml) is added 3-methyl-4-NITROPHENOL (5,94 g, to 38.8 mmol) and diisopropylethylamine (13,5 ml, 77.5 mmol) followed by stirring at 150°C in nitrogen atmosphere. The reaction mixture is cooled to room temperature and contained in a mixture of diisopropylethylamine evaporated under reduced pressure. The resulting residue is distributed between ethyl acetate (150 ml) and 1 N. aqueous sodium hydroxide solution (50 ml). The aqueous layer was extracted with ethyl acetate (50 ml). Obyedinenie the second organic layer is washed with saturated saline and dried over anhydrous sodium sulfate. The solvent is evaporated and get the remainder, which is purified column chromatography on silica gel (eluent: hexane/ethyl acetate = 1/2, ethyl acetate, then ethyl acetate/methanol = 20/1), getting mentioned in the title compound (1.64 g, 34.4 percent) in a solid brown color.

Range1H-NMR (DMSO-d6) δ (ppm): to 2.54 (3H, c), 5,98 (1H, d, J=2.4 Hz), 6,07 (2H, Sirs), 6,23 (1H, DD, J=2,4, 5,6 Hz), 7,14 (1H, DD, J=2,4, 8,8 Hz), 7,25 (1H, d, J=2.4 Hz), 7,89 (1H, d, J=5.6 Hz), 8,10 (1H, d, J=8,8 Hz).

ESI-MS (m/z): 246 [M+H]+.

Example of getting 72

Morpholine-4-carboxylic acid [4-(4-amino-3-methylphenoxy)pyridine-2-yl]amide

To a solution of 4-(3-methyl-4-nitrophenoxy)pyridine-2-ylamine (553 mg, and 2.26 mmol) in tetrahydrofuran (20 ml), add triethylamine (0,471 ml, to 3.38 mmol) under nitrogen atmosphere. Phenylcarbamate (0,424 ml, to 3.38 mmol) are added while cooling on ice, followed by stirring for 20 minutes the Reaction mixture was concentrated under reduced pressure, obtaining a residue, to which is added N,N-dimethylformamide (8.0 ml) and morpholine (of 0.786 ml, of 9.02 mmol) followed by stirring at room temperature for 11 hours. The reaction mixture is distributed between ethyl acetate (60 ml) and water (60 ml). The organic layer was washed with saturated saline, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting residue is dissolved in ethanol (20 ml) and the ATEM type electrolytic iron powder (505 mg, 9,04 mmol), ammonium chloride (967 ml of 18.1 mmol) and water (5 ml) followed by stirring at 80°C for 2 hours. The reaction mixture is cooled to room temperature and filtered to remove insoluble substances. The filtrate is concentrated under reduced pressure and get the remainder, which is purified column chromatography on silica gel (eluent: hexane/ethyl acetate = 1/1, ethyl acetate, then ethyl acetate/methanol = 10/1), getting mentioned in the title compound (283 mg, 38,1%) as a brown oil.

Range1H-NMR (DMSO-d6) δ (ppm): 2,05 (3H, c), 3,39 (4H, m), 3,55 (4H, m), is 4.85 (2H, m), 6.48 in (1H, DD, J=2,4, 5,6 Hz), 6,63-6,70 (2H, m), of 6.73 (1H, c), 7,29 (1H, d, J=2.4 Hz), of 8.04 (1H, d, J=5.6 Hz), 9,13 (1H, c).

Example of getting 73

Pyrrolidin-1-carboxylic acid [4-(4-amino-3-methylphenoxy)pyridine-2-yl]amide

To a solution of 4-(3-methyl-4-nitrophenoxy)pyridin-2-ylamine (553 mg, and 2.26 mmol) in tetrahydrofuran (20 ml), add triethylamine (0,471 ml, to 3.38 mmol) under nitrogen atmosphere. While cooling on ice, add phenylcarbamate (0,424 ml, to 3.38 mmol) followed by stirring for 20 minutes the Reaction mixture was concentrated under reduced pressure, obtaining a residue, to which is added N,N-dimethylformamide (8.0 ml) and pyrrolidine (0,753 ml of 9.02 mmol) followed by stirring at room temperature for 10 minutes the Reaction mixture is distributed between ethyl acetate (60 ml) and water is (60 ml). The organic layer was washed with saturated saline, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting residue is dissolved in ethanol (20 ml) and then add electrolytic iron powder (505 mg, 9,04 mmol), ammonium chloride (967 ml of 18.1 mmol) and water (5 ml) followed by stirring at 80°C for 2 hours. The reaction mixture is cooled to room temperature and filtered to remove insoluble substances. The filtrate is concentrated under reduced pressure and get the remainder, which is purified column chromatography on silica gel (eluent: hexane/ethyl acetate = 1/1, ethyl acetate, then ethyl acetate/methanol = 10/1,) getting mentioned in the title compound (277 mg, 39.2 per cent) in the form of a powder orange color.

Range1H-NMR (DMSO-d6) δ (ppm): 1,80 (4H, m), is 2.05 (3H, c), 3,30 (4H, m), is 4.85 (2H, m), 6,46 (1H, DD, J=2,0, 5.6 Hz), 6,63-6,70 (2H, m), of 6.73 (1H, d, J=2.4 Hz), 7,39 (1H, d, J=2.0 Hz), 8,02 (1H, d, J=5.6 Hz), 8,54 (1H, c).

Example of getting 74

4-(4-Amino-3-methylphenoxy)pyridin-2-ylamine

To a solution of 4-(3-methyl-4-nitrophenoxy)pyridine-2-ylamine (1.64 g, 6,69 mmol) in methanol (75 ml) is added 10% palladium on coal (300 mg), followed by stirring in an atmosphere of hydrogen at room temperature for a period of 14.5 hours. The reaction mixture is filtered to remove the catalyst. The filtrate is concentrated under reduced pressure, and we shall have a rest, which is purified column chromatography on silica gel (eluent: hexane:ethyl acetate = 1:2, ethyl acetate, then ethyl acetate:methanol = 20:1 to 10:1), obtaining mentioned in the title compound (765 mg, 53.1 per cent) in a solid brown color.

Range1H-NMR (CDCl3) δ (ppm):I and 2.14 (3H, c), of 3.45 (2H, Sirs), 4,47 (2H, Sirs), by 5.87 (1H, d, J=2.0 Hz), 6,23 (1H, DD, J=2.0 a, 6,0 Hz), of 6.65 (1H, d, J=8,4 Hz), 6,74 (1H, DD, J=2,8, and 8.4 Hz), 6,77 (1H, d, J=2,8 Hz), the 7.85 (1H, d, J=6.0 Hz).

Example of getting 75

N-[4-(2-Aminopyridine-4-yloxy)-2-were]-N'-(4-forfinal)malonamide

To a solution of 4-(4-amino-3-methylphenoxy)pyridin-2-ylamine (765 mg, 3,55 mmol) in N,N-dimethylformamide (15.0 ml) is added N-(4-forfinal)malonic acid (770 mg, 3,91 mmol), triethylamine (0,544 ml, 3,91 mmol) and hexaphosphate benzotriazol-1-yloxytris(dimethylamino)phosphonium (1.73 g, 3,91 mmol) followed by stirring at room temperature for 13 hours. The reaction mixture is distributed between ethyl acetate (200 ml) and saturated aqueous sodium hydrogen carbonate (80 ml). The organic layer is washed with water and saturated saline, then dried over anhydrous sodium sulfate. The solvent is evaporated, receiving the remainder, which is then subjected to column chromatography on silica gel (ethyl acetate, then ethyl acetate/methanol = 20/1-10/1). The crude product is suspended in ethanol (0.5 ml) and Diatlov the th ether (10 ml). The solid is filtered off, washed with diethyl ether and dried in a stream of air, getting mentioned in the title compound (805 mg, 57.5%, respectively) in the form of a powder pale yellow color.

Range1H-NMR (DMSO-d6) δ (ppm): of 2.25 (3H, c), 3,52 (2H, c), of 5.81 (1H, d, J=2.0 Hz), 5,94 (2H, c), 6,14 (1H, DD, J=2.0 a, 6,0 Hz)6,94 (1H, DD, J=2.0 a, 8,8 Hz), 7,02 (1H, d, J=2.0 Hz), 7,17 (2H, DD, J=9,0, 9.0 Hz), 7,54 (1H, d, J=8,8 Hz), 7,63 (2H, DD, J=5.0 and 9.0 Hz), 7,79 (1H, d, J=6.0 Hz), 9,62 (1H, c), 10,26 (1H, c).

ESI-MS (m/z): 395 [M+H]+.

Example of getting 76

4-(4-Nitro-3-triptoreline)pyridin-2-ylamine

To a solution of 2-amino-4-chloropyridine (2.0 g, 15.6 mmol) in N-organic (16 ml) is added 5-hydroxy-2-nitrobenzotrifluoride (4,85 g and 23.4 mmol) and diisopropylethylamine (8,15 ml, 46.8 mmol), followed by stirring in a nitrogen atmosphere at 150°C for 62 hours. The reaction mixture is cooled to room temperature and diisopropylethylamine evaporated under reduced pressure. The resulting residue is partitioned between a mixture of ethyl acetate:tetrahydrofuran = 1:1 (300 ml) and 1 N. aqueous sodium hydroxide solution (100 ml). The organic layer was washed with 1 N. aqueous sodium hydroxide solution and saturated saline solution in this order, then dried over anhydrous sodium sulfate. The solvent is evaporated and get the remainder, which is purified column chromatography on silica gel (eluent: heptane/ethyl acetate = 1/2, ethyl acetate,then ethyl acetate/methanol = 20/1). The crude product is filtered through silica gel (Fuji Silysia NH). The filtrate is concentrated and receiving solid, which is then suspended in a mixture of diethyl ether:hexane = 1:1, filtered and dried in a stream of air, getting mentioned in the title compound (760 mg, 16.3 per cent) in a solid brown color.

Range1H-NMR (DMSO-d6) δ (ppm): 6,05 (1H, c), x 6.15 (2H, c), 6,30 (1H, m), to 7.61 (1H, d, J=9,2 Hz), to 7.77 (1H, c), to 7.93 (1H, m), compared to 8.26 (1H, d, J=9,2 Hz).

Example of getting 77

4-(4-Amino-3-triptoreline)pyridin-2-ylamine

To a solution of 4-(4-nitro-3-triptoreline)pyridine-2-ylamine (400 mg, of 1.34 mmol) in methanol (20 ml) is added 10% palladium on coal (146 mg) and stirred under hydrogen atmosphere at room temperature for 10 hours. The reaction mixture is filtered to remove the catalyst. The filtrate is concentrated under reduced pressure and get the remainder, which is purified column chromatography on silica gel (eluent: ethyl acetate), obtaining mentioned in the title compound (201 mg, 55.4 per cent) in the form of a brown oil.

Range1H-NMR (CDCl3) δ (ppm): 4,27 (2H, Sirs), 4,56 (2H, Sirs), to 5.85 (1H, d, J=2.4 Hz), to 6.19 (1H, m), 6,74 (1H, d, J=8.6 Hz), of 6.99 (1H, DD, J=2,4, 8.6 Hz), 7,13 (1H, d, J=2.4 Hz), the 7.85 (1H, d, J=6.0 Hz).

An example of retrieving 78

N-[4-(2-Aminopyridine-4-yloxy)-2-triptoreline]-N'-(4-forfinal)malonamide

To a solution of 4-(4-amino-3-triptoreline)pyridine-2-yl is mine (201 mg, 0,747 mmol) in N,N-dimethylformamide (2.0 ml) is added N-(4-forfinal)malonic acid (221 mg, 1.12 mmol), triethylamine (0,156 ml, 1.12 mmol) and hexaphosphate benzotriazol-1-yloxytris(dimethylamino)phosphonium (496 mg, 1.12 mmol) followed by stirring at room temperature for 5 hours. The reaction mixture is distributed between ethyl acetate (100 ml) and water (50 ml). The organic layer was washed with saturated aqueous sodium bicarbonate and saturated saline in this order, then dried over anhydrous sodium sulfate. The solvent is evaporated and get the remainder, which is purified column chromatography on silica gel (eluent: ethyl acetate, then ethyl acetate:methanol = 10:1), obtaining mentioned in the title compound (335 mg, 17.6 per cent) in the form of a brown oil.

Range1H-NMR (CDCl3) δ (ppm): to 3.58 (2H, c), 4,71 (2H, Sirs), 5,95 (1H, d, J=2.0 Hz), 6,28 (1H, DD, J=2.0 a, 6,0 Hz), 7,01? 7.04 baby mortality (2H, m), 7,25 (1H, DD, J=2,8, and 8.4 Hz), was 7.36 (1H, d, J=2,8 Hz), 7,50-rate of 7.54 (2H, m), to 7.93 (1H, d, J=6,0 Hz), by 8.22 (1H, d, J=8,4 Hz), 9,27 (1H, c)9,68 (1H, c).

Example of getting 79

1-Benzyloxy-3-methoxy-4-nitrobenzene

3-Fluoro-4-NITROPHENOL (15,71 g) dissolved in N,N-dimethylformamide (150 ml), then add potassium carbonate (16,59 g) and benzylbromide (14,27 ml) at 60°C, followed by stirring for 3 hours. The reaction mixture is cooled to room temperature and distributed between ethyl acetate is water. The organic layer is washed with water and saturated saline in this order, then dried over anhydrous sodium sulfate. The solvent is evaporated, getting the balance (35,09 g)which is dissolved in methanol (200 ml), then add potassium carbonate (27,64 g) and heated under reflux for 1 hour. The reaction mixture is cooled to room temperature and concentrated under reduced pressure, obtaining a residue, which is then distributed between ethyl acetate and water. The organic layer is washed with water and saturated saline in this order, then dried over anhydrous sodium sulfate. The solvent is evaporated, obtaining a residue, to which is added diethyl ether (200 ml) and stirred. The precipitated crystals are filtered and dried in a stream of air, getting mentioned in the title compound (21,10 g, 81%) as crystals pale yellow color.

Range1H-NMR (CDCl3) δ (ppm): 3,93 (3H, c), 5,14 (2H, c), 6,56-6,62 (2H, m), 7,30 is 7.50 (5H, m), of 8.00 (1H, d, J=9,2 Hz).

Example of getting 80

4-Amino-3-methoxyphenol

1-Benzyloxy-3-methoxy-4-nitrobenzene (11,0 g) dissolved in a mixture of tetrahydrofuran (100 ml) - methanol (100 ml), then add 10% palladium on coal (5.0 g), after which the nitrogen in the system is replaced with hydrogen and stirred overnight. After replacing the nitrogen in the system, the reaction mixture is filtered to remove the TB catalyst, which is washed with tetrahydrofuran, ethyl acetate and methanol in this order. The filtrate is concentrated under reduced pressure and get the remainder, which is dried in vacuum, obtaining specified in the header connection (5,88 g, quantitative yield) as brown powder.

Range1H-NMR (CDCl3) δ (ppm): 3,82 (3H, c), 6,27 (1H, DD, J=2,4, 8.0 Hz), 6,41 (1H, d, J=2.4 Hz), 6,59 (1H, d, J=8.0 Hz).

Example of getting 81

2-Amino-4-(4-amino-3-methoxyphenoxy)pyridine

4-Amino-3-methoxyphenol (5,88 g) dissolved in dimethyl sulfoxide (80 ml) under stirring, then gradually added 60% sodium hydride (1.6 g) in a stream of nitrogen, followed by stirring for 20 minutes Then add 2-amino-4-chloropyridine (2,75 g) and stirred at 160°C for 8 hours. The reaction mixture is cooled to room temperature and distributed between ethyl acetate and water. The organic layer is washed with water and saturated saline in this order, then dried over anhydrous sodium sulfate. The solvent is evaporated under reduced pressure, obtaining a residue, which is purified column chromatography on silica gel (eluent: ethyl acetate, then ethyl acetate:methanol = 9:1). The fractions containing the target compound, concentrate, and get the remainder, to which is added diethyl ether to precipitate crystals. The crystals are filtered and dried in a stream of air, getting listed in the title compound (1.56 g, 34%) as crystals pale brown color.

Range1H-NMR (CDCl3) δ (ppm): of 3.77 (2H, W), a 3.83 (3H, c), 4,34 (2H, W), 5,91 (1H, d, J=2.0 Hz), 6,28 (1H, DD, J=2,0, 5.6 Hz), 6,52-6,56 (2H, m), 6,70 (1H, DD, J=0,4, 8.0 Hz), of 7.90 (1H, d, J=5.6 Hz).

Example of getting 82

2-Amino-4-{3-methoxy-4-[3-(2-phenylacetyl)touraid]phenoxy}pyridine

2-Phenylacetylene (0,198 ml) dissolved in acetonitrile (10 ml) under nitrogen atmosphere, then adding potassium thiocyanate (292 mg) at 60°C and stirred at the same temperature for 3.5 hours. The reaction mixture is cooled to room temperature and add 2-amino-4-(4-amino-3-methoxyphenoxy)pyridine (231.3 of which mg), after which stirring is continued for 2 hours. The reaction mixture is distributed between ethyl acetate and saturated aqueous sodium bicarbonate. The organic layer is washed with water and saturated saline in this order, then dried over anhydrous sodium sulfate. The solvent is evaporated under reduced pressure and get the remainder, which is purified column chromatography on silica gel (eluent: ethyl acetate, then ethyl acetate:methanol = 9:1), obtaining mentioned in the title compound (158 mg, 39%) as a powder pale brown color.

Range1H-NMR (CDCl3) δ (ppm): 3,71 (3H, c), of 3.77 (2H, c)to 5.13 (2H, W), 5,86 (1H, d, J=2.4 Hz), and 6.25 (1H, DD, J=2,4, 6,0 Hz) is 6.54 (1H, d, J=2.4 Hz), to 6.67 (1H, DD, J=2,4, 8,8 Hz), 7,30 was 7.45 (6H, m), of 7.70 (1H, Sirs), of 7.82 (1H, d, J=6.0 Hz), 8,35 (1H, d, J=8,8 Hz).

Example of getting 83

Benzyl N-(4-AMINOPHENYL)carbamate

1,4-Diaminobenzene (1,081 g) dissolved in tetrahydrofuran (50 ml) in a nitrogen atmosphere under stirring, then add dropwise a triethylamine (2,01 ml) and benzylchloride (1,71 ml), cooling in a bath with ice, and then gradually increase the temperature to room temperature. After 7 hours the reaction mixture is added saturated aqueous sodium hydrogen carbonate solution and extracted with ethyl acetate. The organic layer was washed with saturated saline and dried over anhydrous sodium sulfate. The solvent is evaporated under reduced pressure, obtaining a residue, which is purified column chromatography on silica gel (eluent: hexane:ethyl acetate = 1:1). The fractions containing the target compound, concentrate, and get the remainder, which is then suspended in a mixture of hexane-ethyl acetate. The solid is filtered off and dried in a stream of air, getting mentioned in the title compound (1,093 g, 45%) as a powder pale yellow color.

Range1H-NMR (CDCl3) δ (ppm): of 3.56 (2H, Sirs), is 5.18 (2H, c), of 6.45 (1H, Sirs), 6,60-6,70 (2H, m), 7,10-7,20 (2H, m), 7,30 is 7.50 (5H, m).

Example of getting 84

Benzyl N-[4-(6-aminopyrimidine-4-ylamino)phenyl]carbamate

6-Amino-4-chloropyrimidine (259 mg) dissolved in 2-ethoxyethanol (10 ml), the eat added benzyl N-(4-AMINOPHENYL)carbamate (533 mg) and 2 N. HCl (2 ml) followed by stirring at 120°C during the night. The reaction mixture is cooled to room temperature and distributed between ethyl acetate and saturated aqueous sodium bicarbonate. The organic layer was washed with saturated saline and dried over anhydrous sodium sulfate. The solvent is evaporated under reduced pressure, obtaining a residue, which is purified column chromatography on silica gel (eluent: ethyl acetate:methanol = 95:5). The fractions containing the target compound, concentrate, and get the remainder, to which is added a mixture of ethyl acetate-hexane to precipitate crystals. The solid is filtered and dried in a stream of air, getting mentioned in the title compound (313,1 mg, 47%) as crystals milky color.

Range1H-NMR (CDCl3) δ (ppm): 4,59 (2H, Sirs), with 5.22 (2H, c), 5,72 (1H, m), 6,53 (1H, Sirs), 6,69 (1H, Sirs), 7,20 (2H, d, J=8,8 Hz), 7,30 is 7.50 (7H, m), to 8.20 (1H, c).

An example of retrieving 85

Benzyl N-{4-[6-(pyrrolidin-1-ylcarbonyl)aminopyrimidine-4-ylamino]phenyl]carbamate

Benzyl N-[4-(6-aminopyrimidine-4-ylamino)phenyl]carbamate (313 mg) was dissolved in tetrahydrofuran (10 ml) under nitrogen atmosphere, then added dropwise a triethylamine (0,78 ml) and phenylcarbamate (0.35 ml), cooling in a bath with ice, followed by stirring at room temperature for 30 minutes To the reaction mixture add pyrrol the Dean (1.0 ml) and N,N-dimethylformamide (2 ml), then stirring is continued at room temperature overnight. The reaction mixture is distributed between ethyl acetate and water. The organic layer was washed with saturated saline and dried over anhydrous sodium sulfate. The solvent is evaporated under reduced pressure and get the remainder, which is purified column chromatography on silica gel (eluent: ethyl acetate, then ethyl acetate:methanol = 95:5), receiving specified in the title compound (210 mg, 52%) as a powder pale yellow color.

Range1H-NMR (CDCl3) δ (ppm): 1,90-2,00 (4H, m), 3,40-to 3.50 (4H, m), 5,20 (2H, c), of 6.73 (1H, Sirs), to 6.75 (1H, Sirs), to 6.95 (1H, Sirs), 7,28-7,47 (10H, m), of 8.28 (1H, d, J=1.2 Hz).

An example of retrieving 86

4-(4-Aminophenylamino)-6-[(pyrrolidin-1-yl)carbylamine]pyrimidine

Benzyl N-{4-[6-(pyrrolidin-1-ylcarbonyl)aminopyrimidine-4-ylamino]phenyl]carbamate (210 mg) dissolved in a mixture of tetrahydrofuran (5 ml) - methanol (5 ml), then add 10% palladium on coal (200 mg) in a nitrogen atmosphere, after which the nitrogen in the system is replaced with hydrogen and stirred for 5 hours. After replacing the nitrogen in the system, the reaction mixture is filtered to remove the catalyst which is washed with tetrahydrofuran and ethanol in that order. The filtrate is concentrated under reduced pressure, obtaining a residue, to which is added a mixture of hexane-ethyl acetate to precipitate crystals. Krist is lly filtered and dried in a stream of air, getting listed in the title compound (103 mg, 71%) as white crystals.

Range1H-NMR (CDCl3) δ (ppm): 1,90-2,00 (4H, m), 3,30-to 3.50 (4H, m)to 3.64 (2H, Sirs), 6,55 (1H, Sirs), 6,68-of 6.71 (2H, m), 6.90 to (1H, Sirs), 7,10 (2H, d, J=8,4 Hz), 7,33 (1H, c), 8,24 (1H, c).

Example of getting 87

Benzyl N-[4-(2-aminopyrimidine-4-ylamino)phenyl]carbamate

2-Amino-4-chloropyridine (257 mg) dissolved in 2-ethoxyethanol (10 ml), then add benzyl N-(4-AMINOPHENYL)carbamate (533 mg) and pyridine hydrochloride (462 mg), followed by stirring at 120°C during the night. The reaction mixture is cooled to room temperature and distributed between ethyl acetate and saturated aqueous sodium bicarbonate. The organic layer was washed with saturated saline and dried over anhydrous sodium sulfate. The solvent is evaporated under reduced pressure, obtaining a residue, which is purified column chromatography on silica gel (Fuji Silysia NH, eluent: ethyl acetate, then ethyl acetate:methanol = 95:5). The fractions containing the target compound, concentrate, and get the remainder, to which is added a mixture of ethyl acetate-hexane to precipitate crystals. The solid is filtered and dried in a stream of air, getting mentioned in the title compound (321,5 mg, 48%) as crystals pale brown color.

Range1H-NMR (CDCl3) δ (ppm): to 4.28 (2H, Sirs), to 5.21 (2H, c), USD 5.76 (1H, c), 5,95 (H, m), 6,17 (1H, DD, J=2.0 a, 6,0 Hz), 6,66 (1H, Sirs), 7,12 (2H, d, J=8,8 Hz), 7,30 was 7.45 (7H, m), 7,79 (1H, d, J=6.0 Hz).

Example of getting 88

4-(4-Aminophenylamino)-2-[(pyrrolidin-1-yl)carbylamine]pyridine

Benzyl N-[4-(2-aminopyridine-4-ylamino)phenyl]carbamate (321 mg) was dissolved in tetrahydrofuran (10 ml) under nitrogen atmosphere, then added dropwise a triethylamine (0,803 ml) and phenylcarbamate (0,36 ml), cooling in a bath with ice, followed by stirring at room temperature for 1 hour. To the reaction mixture add pyrrolidine (0.8 ml) and N,N-dimethylformamide (2 ml) followed by stirring at room temperature over night. The reaction mixture is distributed between ethyl acetate and water. The organic layer was washed with saturated saline and dried over anhydrous sodium sulfate. The solvent is evaporated under reduced pressure, obtaining the remainder (950 mg)which is dissolved in dimethyl sulfoxide (5.0 ml), and then add 5 N. aqueous sodium hydroxide solution (1.0 ml) followed by stirring at 100°C for 30 minutes, the Reaction mixture was cooled to room temperature and distributed between ethyl acetate and water. The organic layer is washed with water and saturated saline in this order, then dried over anhydrous sodium sulfate. The solvent is evaporated and get the remainder, which purify column chromatograph is she on silica gel (Fuji Silysia NH, eluent: ethyl acetate, then ethyl acetate:methanol = 95:5), receiving specified in the title compound (116 mg, 41%) as crystals pale yellow color.

Range1H-NMR (CDCl3) δ (ppm): 1,90-2,00 (4H, m), 3,40-to 3.50 (4H, m)to 3.64 (2H, Sirs), of 5.82 (1H, Sirs), of 6.31 (1H, m), 6,65 to 6.75 (2H, m), 6.90 to (1H, Sirs), 6,99-7,03 (2H, m), 7,53 (1H, d, J=2.4 Hz), 7,80 (1H, d, J=6.0 Hz).

Example of getting 89

6-(2-Fluoro-4-nitrophenoxy)pyrimidine-4-ylamine

2-Fluoro-4-NITROPHENOL (1,736 g) dissolved in dimethyl sulfoxide (10 ml) and add sodium hydride (400 mg) followed by stirring for 20 minutes Add 4-amino-6-chloropyrimidine (648 mg) and stirred at 100°C for 45 minutes Then the reaction mixture is heated to 120°C and stirred for 1 hour and 25 minutes Then the reaction mixture is heated to 140°C and stirred overnight. The reaction mixture is cooled to room temperature, add 1 N. aqueous solution of sodium hydroxide (10 ml), stirred and extracted with ethyl acetate. The organic layer was washed with 1 N. aqueous sodium hydroxide solution, water and saturated saline in this order, then dried over anhydrous sodium sulfate. The solvent is evaporated under reduced pressure, obtaining a residue, which is purified column chromatography on silica gel (eluent: hexane:ethyl acetate = 1:2). The solvent is evaporated under reduced pressure, obtaining the remainder, to the which are suspended in a mixture of diethyl ether (7 ml) - hexane (3.5 ml). The solid is filtered off and dried in a stream of air, getting mentioned in the title compound (201 mg, 16,0%) in the form of a powder pale brown color.

Range1H-NMR (DMSO-d6) δ (ppm): of 6.02 (1H, m), 7,06 (2H, Sirs), 7,60 (1H, DD, J=8.0 a, 8,8 Hz), of 8.04 (1H, m), 8,10-8,19 (1H, m), 8,30 (1H, DD, J=2, 10 Hz).

Example of getting 90

Pyrrolidin-1-carboxylic acid [6-(2-fluoro-4-nitrophenoxy)pyrimidine-4-yl]amide

4-Amino-6-(2-fluoro-4-nitrophenoxy)pyrimidine (100 mg) dissolved in tetrahydrofuran (3 ml) under nitrogen atmosphere, then added dropwise a triethylamine (0,112 ml) and phenylcarbamate (0.100 ml) followed by stirring for 1.5 hours. To the reaction mixture add pyrrolidine (0,313 ml) and stirred for 30 minutes, the Reaction mixture was distributed between ethyl acetate and saturated aqueous ammonium chloride. The organic layer was washed with saturated aqueous ammonium chloride, water and saturated saline in this order, then dried over anhydrous sodium sulfate. The solvent is evaporated under reduced pressure, obtaining a residue, which is purified column chromatography on silica gel (Fuji Silysia NH, eluent: hexane:ethyl acetate = 2:1). The solvent is evaporated under reduced pressure, obtaining a residue that is distributed between ethyl acetate and 1 N. aqueous sodium hydroxide solution. The organic layer is washed with water and saturated saline in this order, then dried over anhydrous sodium sulfate. The solvent is evaporated under reduced pressure and get the remainder, which is then dried in vacuum, obtaining specified in the header connection (96,6 mg, 69.5 per cent) in a solid yellow color.

Range1H-NMR (CDCl3) δ (ppm): 2,02 (4H, m), 3,51 (4H, m), 7,22 (1H, m), 7,41 (1H, m), 7,81 (1H, d, J=1.2 Hz), 8.07-a of 8.15 (2H, m), 8,32 (1H, m).

Example of getting 91

Pyrrolidin-1-carboxylic acid [6-(4-amino-2-pertenece)pyrimidine-4-yl]amide

Pyrrolidin-1-carboxylic acid [6-(2-fluoro-4-nitrophenoxy)pyrimidine-4-yl]amide (610 mg) dissolved in a mixture of ethanol (15 ml) - water (3 ml), then add electrolytic iron powder (610 mg) and ammonium chloride (1.20 g), then heated under reflux for 30 minutes, the Reaction mixture was cooled to room temperature, add a mixture of ethyl acetate-tetrahydrofuran (1:1) and stirred. The mixture is filtered through celite to remove insoluble substances, which is washed with ethyl acetate and water. The organic layer of the filtrate washed with water and saturated saline in this order, then dried over anhydrous sodium sulfate. The solvent is evaporated under reduced pressure, obtaining a residue, which is purified column chromatography on silica gel (Fuji Silysia NH, eluent: hexane:ethyl acetate = 1:1 to 1:5). The fractions containing the target compounds is s, concentrate under reduced pressure and dried in vacuum, obtaining mentioned in the title compound (495 mg, 88.6 per cent) in the form of a solid pale yellow color.

Range1H-NMR (CDCl3) δ (ppm): 1,99 (4H, m), of 3.48 (4H, m), 3,74 (2H, m), to 6.43 (1H, m), 6,44-6,53 (1H, m)6,94 (1H, m), 7,17 (1H, m), 7,63 (1H, c), of 8.37 (1H, c).

Example of getting 92

Morpholine-4-carboxylic acid [6-(2-fluoro-4-nitrophenoxy)pyrimidine-4-yl]amide

4-Amino-6-(2-fluoro-4-nitrophenoxy)pyrimidine (89 mg) was dissolved in tetrahydrofuran (3 ml) under nitrogen atmosphere, then added dropwise a triethylamine (0,099 ml) and phenylcarbamate (0,089 ml), cooling in a bath with ice, followed by stirring at room temperature for 45 minutes To the reaction mixture are added morpholine (0,249 ml) followed by stirring at room temperature over night. The reaction mixture is distributed between ethyl acetate and saturated aqueous ammonium chloride. The organic layer was washed with saturated aqueous ammonium chloride, water and saturated saline in this order, then dried over anhydrous sodium sulfate. The solvent is evaporated under reduced pressure, obtaining a residue, which is purified column chromatography on silica gel (Fuji Silysia NH, eluent: hexane:ethyl acetate = 1:1). The fractions containing the target compound are concentrated under reduced pressure and dried in VA is uume, getting listed in the title compound (an 80.2 mg, 62,0%) as a colourless solid.

Range1H-NMR (CDCl3) δ (ppm): 3,55 (4H, m), of 3.77 (4H, m), of 7.36-7,44 (2H, m), 7,74 (1H, d, J=0.8 Hz), 8,06-8,16 (2H, m), with 8.33 (1H, m).

Example of getting 93

Morpholine-4-carboxylic acid [6-(4-amino-2-pertenece)pyrimidine-4-yl]amide

Morpholine-4-carboxylic acid [6-(2-fluoro-4-nitrophenoxy)pyrimidine-4-yl]amide (107 mg) dissolved in a mixture of ethanol (5 ml) - water (1 ml), then add electrolytic iron powder (110 mg) and ammonium chloride (220 mg), and then heated under reflux for 30 minutes, the Reaction mixture was cooled to room temperature and add a mixture of ethyl acetate-tetrahydrofuran (1:1), followed by stirring. The reaction mixture was filtered through celite to remove insoluble substances, which is washed with ethyl acetate and water. The organic layer of the filtrate washed with water and saturated saline in this order, then dried over anhydrous sodium sulfate. The solvent is evaporated under reduced pressure, obtaining a residue, which is purified column chromatography on silica gel (Fuji Silysia NH, eluent: hexane:ethyl acetate = 1:1). The fractions containing the target compound are concentrated under reduced pressure and dried in vacuum, obtaining specified in the header of the connection (and 82.4 mg, up 85.2%) in the form of solid substances is yellow.

Range1H-NMR (CDCl3) δ (ppm): to 3.52 (4H, m), 3,74 (6H, m), 6.42 per-6,48 (1H, m), 6,50 (1H, m), 6,97 (1H, m), 7,52 (1H, m), 7,66 (1H, m), of 8.37 (1H, m).

Example of getting 94

Piperidine-1-carboxylic acid [6-(2-fluoro-4-nitrophenoxy)pyrimidine-4-yl]amide

4-Amino-6-(2-fluoro-4-nitrophenoxy)pyrimidine (300 mg) is dissolved in tetrahydrofuran (5 ml) under nitrogen atmosphere, then added dropwise a triethylamine (0,335 ml) and phenylcarbamate (0,301 ml), cooling in a bath with ice, followed by stirring at room temperature for 45 minutes To the reaction mixture are added piperidine (0,446 ml) and stirred at room temperature for 45 minutes, the Reaction mixture was distributed between ethyl acetate and saturated aqueous ammonium chloride. The organic layer was washed with saturated aqueous ammonium chloride, 1 N. aqueous sodium hydroxide solution, water and saturated saline in this order, then dried over anhydrous sodium sulfate. The solvent is evaporated under reduced pressure, obtaining a residue, which is purified column chromatography on silica gel (eluent: hexane:ethyl acetate = 3:2). The fractions containing the target compound are concentrated under reduced pressure and dried in vacuum, obtaining specified in the header of the connection (of 275.4 mg, 63.5 per cent) in the form of oil pale yellow color.

Range1H-NMR (CDCl3) δ (ppm): 1,54-1,76 (4, m)a 3.50 (6H, m), 7,38-of 7.48 (2H, m), 7,74 (1H, c), 8,06-8,16 (2H, m), 8,32 (1H, c).

Example obtain 95

Piperidine-1-carboxylic acid [6-(4-amino-2-pertenece)pyrimidine-4-yl]amide

Piperidine-1-carboxylic acid [6-(2-fluoro-4-nitrophenoxy)pyrimidine-4-yl]amide (273 mg) dissolved in a mixture of ethanol (15 ml) - water (3 ml), then add electrolytic iron powder (275 mg) and ammonium chloride (550 mg), and then heated under reflux for 30 minutes, the Reaction mixture was cooled to room temperature, add a mixture of ethyl acetate-tetrahydrofuran (1:1) and stirred. The reaction mixture was filtered through celite to remove insoluble substances, which is washed with ethyl acetate and water. The organic layer of the filtrate washed with water and saturated saline in this order, then dried over anhydrous sodium sulfate. The solvent is evaporated under reduced pressure, obtaining a residue, which is purified column chromatography on silica gel (Fuji Silysia NH, eluent: hexane:ethyl acetate = 1:1 to 1:5). The fractions containing the target compound are concentrated under reduced pressure and dried in vacuum, obtaining specified in the header connection (235,8 mg, 94,1%) as a solid pale yellow color.

Range1H-NMR (CDCl3) δ (ppm): 1,63 (6H, m), 3,47 (4H, m), 3,74 (2H, Sirs), of 6.45 (1H, m), 6,50 (1H, DD, J=2, 12 Hz), 6,97 (1H, m), of 7.36 (1H, Sirs), 7,56 (1H, m), at 8.36 (1H, m).

An example of retrieving 96

3-[6-(2-Fluoro-4-nitrophenoxy)pyrimidine-4-yl]-1,1-dimethyloxetane

4-Amino-6-(2-fluoro-4-nitrophenoxy)pyrimidine (500 mg) dissolved in tetrahydrofuran (10 ml) under nitrogen atmosphere and added dropwise the triethylamine (0,418 ml) and phenylcarbamate (0,376 ml), cooling in a bath with ice, followed by stirring at room temperature for 1 hour and 10 minutes Then add triethylamine (0,139 ml) and phenylcarbamate (0,125 ml), cooling in a bath with ice, followed by stirring at room temperature for 30 minutes Then add triethylamine (0,139 ml) and phenylcarbamate (0,125 ml) followed by stirring at room temperature for 30 minutes To the reaction mixture are added 2M solution of dimethylamine in methanol) (5.0 ml), followed by stirring at room temperature over night. The reaction mixture is distributed between ethyl acetate and saturated aqueous ammonium chloride. The organic layer was washed with saturated aqueous ammonium chloride, saturated aqueous sodium bicarbonate, water and saturated saline in this order, then dried over anhydrous sodium sulfate. The solvent is evaporated under reduced pressure, obtaining a residue, which is then suspended in diethyl ether. The solid is filtered and dried in a stream of air, floor the tea is specified in the header connection (378,9 mg, 59,0%) in the form of a powder pale yellow color.

Range1H-NMR (CDCl3) δ (ppm): is 3.08 (6H, c), 7,41 (2H, m), to 7.77 (1H, Sirs), 8,11 (2H, m), 8,32 (1H, Sirs).

Example of getting 97

3-[6-(4-Amino-2-pertenece)pyrimidine-4-yl]-1,1-dimethyloxetane

3-[6-(2-Fluoro-4-nitrophenoxy)pyrimidine-4-yl]-1,1-dimethyloxetane (227 mg) dissolved in a mixture of ethanol (15 ml) - water (3 ml) and add electrolytic iron powder (230 mg) and ammonium chloride (460 mg), and then heated under reflux for 30 minutes, the Reaction mixture was cooled to room temperature, add a mixture of ethyl acetate-tetrahydrofuran (1:1) and stirred. The reaction mixture was filtered through celite to remove insoluble substances, which is washed with ethyl acetate and water. The organic layer of the filtrate washed with water and saturated saline in this order, then dried over anhydrous sodium sulfate. The solvent is evaporated under reduced pressure, obtaining a residue, which is purified column chromatography on silica gel (eluent: hexane:ethyl acetate = 1:3). The fractions containing the target compound are concentrated under reduced pressure, obtaining a residue which is suspended in a mixture of diethyl ether (4 ml) - hexane (4 ml). The solid is filtered and dried in a stream of air, getting mentioned in the title compound (172 mg, 83.4%of) in the form of solids Bleue is but yellow.

Range1H-NMR (CDCl3) δ (ppm): 3,05 (6H, m), 3,74 (2H, Sirs), of 6.45 (1H, m), 6,50 (1H, m), 6,97 (1H, m), 7,32 (1H, Sirs), 7,60 (1H, d, J=1.2 Hz), of 8.37 (1H, d, J=1.2 Hz).

An example of retrieving 98

N-{4-[6-(3,3-Dimethylurea)pyrimidine-4-yloxy]-3-forfinal}malonic acid benzyl ester

3-[6-(4-Amino-2-pertenece)pyrimidine-4-yl]-1,1-dimethyloxetane (92.0 mg) dissolved in N,N-dimethylformamide (2 ml) in nitrogen atmosphere, then add monobenzoyl ester of malonic acid (184,0 mg), triethylamine (0,132 ml) and hexaflurophosphate (1H-1,2,3-benzotriazol-1 iloxi)[three(dimethylamino)]phosphonium (419 mg) at 50°C, followed by stirring at the same temperature for 1 hour. The reaction mixture is cooled to room temperature and distributed between ethyl acetate and saturated aqueous sodium bicarbonate. The organic layer was washed with saturated aqueous sodium bicarbonate, saturated aqueous ammonium chloride, water and saturated saline in this order, then dried over anhydrous sodium sulfate. The solvent is evaporated under reduced pressure, obtaining a residue, which is purified column chromatography on silica gel (eluent: hexane:ethyl acetate = 1:1 to 1:5). The fractions containing the target compound are concentrated under reduced pressure, obtaining specified in the header connection (119,4 mg, 80,8%) as a colourless mA is La.

Range1H-NMR (CDCl3) δ (ppm): a 3.06 (6H, c), 3,53 (2H, c), of 5.24 (2H, c), 7,12-of 7.25 (2H, m), 7,35-7,46 (6H, m), the 7.65 (1H, c), to 7.68 (1H, DD, J=2, 12 Hz), a 8.34 (1H, c), to 9.32 (1H, Sirs).

Example of getting 99

N-{4-[6-(3,3-Dimethylurea)pyrimidine-4-yloxy]-3-forfinal}malonic acid

N-{4-[6-(3,3-Dimethylurea)pyrimidine-4-yloxy]-3-forfinal}malonic acid benzyl ester (119 mg) dissolved in a mixture of tetrahydrofuran (3 ml) - methanol (3 ml) and add 10% palladium on coal (54 mg) in a nitrogen atmosphere, after which the nitrogen in the system is replaced with hydrogen and stirred for 1 hour. After replacing the nitrogen in the system, the catalyst removed from the reaction mixture by filtration and washed with methanol. The filtrate is concentrated under reduced pressure, obtaining a residue which is suspended in a mixture of diethyl ether-hexane (1:1). The solid is filtered and dried in air stream, receiving specified in the header connection (with 76.8 mg, 79.8 per cent) in the form of a solid white color.

Range1H-NMR (DMSO-d6) δ (ppm): 2,94 (6H, c), 3,17 (1H, Sirs), 3,18-of 3.54 (2H, m), 7,44-of 7.48 (2H, m), of 7.36 (1H, d, J=1.2 Hz), 7,74 (1H, m), 8,39 (1H, d, J=1.2 Hz), of 9.56 (1H, Sirs), or 10.6 (1H, Sirs).

Example 100

N-(3-Fluoro-4-{6-[(pyrrolidin-1-carbonyl)amino]pyrimidine-4-yloxy}phenyl)malonic acid benzyl ester

Pyrrolidin-1-carboxylic acid [6-(4-amino-2-pertenece)pyrimidine-4-yl]amide (290 mg) was dissolved in N,N-dimethylformamide (3 ml) in an atmosphere of AZ is the then add monobenzoyl ester of malonic acid (534 mg), triethylamine (0,383 ml) and hexaflurophosphate (1H-1,2,3-benzotriazol-1 iloxi)[three(dimethylamino)]phosphonium (1.22 g) at 50°C, followed by stirring for 30 minutes the Reaction mixture is cooled to room temperature and distributed between ethyl acetate and saturated aqueous sodium bicarbonate. The organic layer was washed with saturated aqueous sodium bicarbonate, saturated aqueous ammonium chloride, water and saturated saline in this order, then dried over anhydrous sodium sulfate. The solvent is evaporated under reduced pressure, obtaining a residue, which is purified column chromatography on silica gel (eluent: hexane:ethyl acetate = 1:1 to 1:2). The fractions containing the target compound are concentrated under reduced pressure, obtaining specified in the header connection (523,7 mg, quantitative yield) as oil pale yellow color.

Range1H-NMR (CDCl3) δ (ppm): 2,00 (4H, m), 3,49 (4H, m), 3,53 (2H, c), of 5.24 (2H, c), 7,10-of 7.25 (3H, m), 7,39 (4H, m), 7,68 (2H, m), 8,02 (1H, Sirs), to 8.34 (1H, m), was 9.33 (1H, Sirs).

An example of retrieving 101

N-(3-Fluoro-4-{6-[(pyrrolidin-1-carbonyl)amino]pyrimidine-4-yloxy}phenyl)malonic acid

N-(3-Fluoro-4-{6-[(pyrrolidin-1-carbonyl)amino]pyrimidine-4-yloxy}phenyl}malonic acid benzyl ester (430 mg) solution of the Ute in a mixture of tetrahydrofuran (13 ml) - methanol (13 ml), add 10% palladium on coal (191 mg) in a nitrogen atmosphere, after which the nitrogen in the system is replaced with hydrogen and stirred for 30 minutes, After replacement of nitrogen in the system, the catalyst removed from the reaction mixture by filtration and washed with methanol. The filtrate is concentrated under reduced pressure, obtaining a residue which is suspended in a mixture of diethyl ether-hexane (1:1). The solid is filtered and dried in a stream of air, getting mentioned in the title compound (361,5 mg, quantitative yield) as a solid pale yellow color.

Range1H-NMR (DMSO-d6) δ (ppm): to 1.83 (4H, Sirs), 3,10-3,50 (7H, m), 7,32 (2H, m), 7,45 (1H, c), 7,74 (1H, m), 8,39 (1H, m), 9,40 (1H, Sirs), 10,50 (1H, Sirs).

Example of getting 102

[1,4']Bipyridinyl-1'-carboxylic acid [6-(4-nitro-2-pertenece)pyrimidine-4-yl]amide

4-Amino-6-(2-fluoro-4-nitrophenoxy)pyrimidine (40 mg) dissolved in tetrahydrofuran (2 ml) in nitrogen atmosphere, then added dropwise a triethylamine (0,045 ml) and phenylcarbamate (0,040 ml) followed by stirring at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure, obtaining a residue which is then dissolved in N,N-dimethylformamide (2 ml). Add 4-(piperidine-1-yl)piperidine (108 mg) and stirred for 10 minutes, the Reaction mixture was distributed between ethyl acetate and saturated podnimetsia ammonium chloride. The organic layer was washed with saturated aqueous ammonium chloride, water and saturated saline in this order, then dried over anhydrous sodium sulfate. The solvent is evaporated under reduced pressure, obtaining a residue, which is purified column chromatography on silica gel (Fuji Silysia NH, eluent: hexane:ethyl acetate = 1:1 to 1:2). The fractions containing the target compound are concentrated under reduced pressure and dried in vacuum, obtaining specified in the header connection (43,9 mg, 61.7 per cent) in a solid yellow color.

Range1H-NMR (CDCl3) δ (ppm): 1,36-to 1.82 (8H, m), with 1.92 (2H, m), 2,52 (5H, m)to 2.94 (2H, m), is 4.15 (2H, m), 7,41 (1H, m), 7,46 (1H, m), 7,73 (1H, m), 8,11 (2H, m), 8,32 (1H, m).

Example of getting 103

4-(Pyrrolidin-1-yl)piperidine-1-carboxylic acid [6-(4-amino-2-pertenece)pyrimidine-4-yl]amide

4-Amino-6-(2-fluoro-4-nitrophenoxy)pyrimidine (50 mg) dissolved in tetrahydrofuran (3 ml) under nitrogen atmosphere, then added dropwise a triethylamine (0,056 ml) and phenylcarbamate (0,050 ml) followed by stirring at room temperature for 30 minutes, the Reaction mixture was concentrated under reduced pressure, obtaining a residue which is then dissolved in N,N-dimethylformamide (3 ml). Add 4-(pyrrolidin-1-yl)piperidine (123 mg) and stirred at room temperature for 2 hours. The reaction mixture is distributed between the y ethyl acetate and saturated aqueous sodium bicarbonate. The organic layer was washed with saturated aqueous sodium bicarbonate, water and saturated saline in this order, then dried over anhydrous sodium sulfate. The solvent is evaporated under reduced pressure, obtaining a residue, which is purified column chromatography on silica gel (Fuji Silysia NH, eluent: hexane:ethyl acetate = 1:5). The solvent is evaporated under reduced pressure and dried in vacuum, obtaining the crude 4-(pyrrolidin-1-yl)piperidine-1-carboxylic acid [6-(2-fluoro-4-nitrophenoxy)pyrimidine-4-yl]amide. The crude product (86 mg) dissolved in a mixture of tetrahydrofuran (2 ml) - methanol (2 ml), add 10% palladium on coal (43 mg) in an atmosphere of nitrogen, then the nitrogen in the system is replaced with hydrogen and stirred overnight. After replacing the nitrogen in the system, the catalyst removed from the reaction mixture by filtration and washed with methanol. The filtrate is concentrated under reduced pressure, obtaining a residue, which is purified column chromatography on silica gel (Fuji Silysia NH, eluent: hexane:ethyl acetate = 1:5, then ethyl acetate). The fractions containing the target compound are concentrated under reduced pressure, obtaining specified in the header of the connection (of 53.5 mg, 66,8%).

Range1H-NMR (DMSO-d6) δ (ppm): 1,31 (2H, m)of 1.66 (4H, m), is 1.81 (2H, m), and 2.14 (1H, m), 2,47 (4H, m), of 2.92 (2H, m), of 3.97 (2H, m), and 5.30-5,42 (2H, m), 6,37 (1H, DD, J=2.0 a, 8,8 Hz), 6,46 (1H, m)6,94 (1, DD, J=8,8, 8,8 Hz), 7.23 percent (1H, m), of 8.37 (1H, m), of 9.75 (1H, Sirs).

Example of getting 104

3-[4-(4-Amino-2-pertenece)pyridine-2-yl]-1-methyl-1-[3-(4-methylpiperazin-1-yl)propyl]urea

4-(2-Fluoro-4-nitrophenoxy)pyridin-2-ylamine (200 mg) is dissolved in tetrahydrofuran (8 ml) under nitrogen atmosphere at room temperature was added drop wise addition of triethylamine (0,336 ml) and phenylcarbamate (0,302 ml) and stirred for 30 minutes, the Reaction mixture was concentrated under reduced pressure, obtaining a residue which is then dissolved in N,N-dimethylformamide (5 ml). Add N-methyl-N-[3-(4-methylpiperazin-1-yl)propyl]amine (0,300 ml) followed by stirring at room temperature over night. Add another portion of N-methyl-N-[3-(4-methylpiperazin-1-yl)propyl]amine (0,200 ml) and stirred at room temperature for 1 day. The reaction mixture is distributed between ethyl acetate and saturated aqueous ammonium chloride. The organic layer was washed with saturated aqueous ammonium chloride, water and saturated saline in this order, then dried over anhydrous sodium sulfate. The solvent is evaporated under reduced pressure, obtaining a residue, which is purified column chromatography on silica gel (Fuji Silysia NH, eluent: heptane:ethyl acetate = 1:1). The solvent is evaporated under reduced pressure, obtaining the crude 3-[4-(2-fluoro-4-NITROPHENOL and)pyridine-2-yl]-1-methyl-1-[3-(4-methylpiperazin-1-yl)propyl]urea. The crude product (357 mg) dissolved in a mixture of tetrahydrofuran (8 ml) - methanol (8 ml), add 10% palladium on coal (170 mg) in a nitrogen atmosphere, after which the nitrogen in the system is replaced with hydrogen and stirred for 2 hours. After replacing the nitrogen in the system, the catalyst removed from the reaction mixture by filtration and washed with methanol. The filtrate is concentrated under reduced pressure, obtaining a residue, which is purified column chromatography on silica gel (Fuji Silysia NH, eluent: heptane:ethyl acetate = 1:1, then ethyl acetate). The fractions containing the target compound, concentrate, and get the remainder, which is then suspended in a mixture of diethyl ether-hexane (2:1). The solid is filtered and dried in a stream of air, getting mentioned in the title compound (91,0 mg, 27.3 per cent) in the form of a powder pale yellow color.

Range1H-NMR (CDCl3) δ (ppm): of 1.65 (2H, m), 1.77 in (2H, m), 2,33 (3H, c), 2,39 (2H, t, J=6.0 Hz), 2,50 (2H, Sirs), to 2.66 (4H, m), 2,90 (3H, c), to 3.38 (2H, t, J=6.0 Hz), 3,64-of 3.80 (2H, m), 6,39-6,53 (3H, m), to 6.95 (1H, m), 7,56 (1H, c), of 8.00 (1H, d, J=1,2, 5,6 Hz), of 9.30 (1H, Sirs).

Example of getting 105

[6-(2-Fluoro-4-nitrophenoxy)pyrimidine-4-yl]carbamino acid phenyl ester

6-(2-Fluoro-4-nitrophenoxy)pyrimidine-4-ylamine (400 mg) dissolved in tetrahydrofuran (16 ml) under nitrogen atmosphere, then added dropwise a triethylamine (0,669 ml) and phenylcarbamate (0,602 ml), cooling in a bath with ice, after which reacciona the mixture is heated to room temperature and stirred for 10 minutes The reaction mixture is distributed between ethyl acetate (30 ml) and saturated aqueous sodium hydrogen carbonate (20 ml). The organic layer was washed with saturated aqueous sodium hydrogen carbonate (20 ml), water (20 ml) and saturated saline (20 ml) in this order, then dried over anhydrous sodium sulfate. The solvent is evaporated and get the remainder, which is purified column chromatography on silica gel (Fuji Silysia NH, eluent: ethyl acetate). The fractions containing the target compound, concentrate, and get the remainder, which is then suspended in a mixture of diethyl ether (4 ml) - hexane (4 ml). The solid is filtered and dried in a stream of air, getting mentioned in the title compound (396 mg, 66,8%) in the form of a powder pale yellow color.

Range1H-NMR (CDCl3) δ (ppm): 7,14-of 7.25 (2H, m), 7,26-to 7.35 (1H, m), 7,38-of 7.48 (3H, m), 7,72 (1H, d, J=0.8 Hz), 8,06-8,18 (2H, m), 8,49 (1H, d, J=0.8 Hz), 8,93 (1H, Sirs).

ESI-MS (m/z) (neg.): 369 [M-H]-.

Example of getting 106

3-[6-(4-Amino-2-pertenece)pyrimidine-4-yl]-1-methyl-1-(1-methylpiperidin-4-yl)urea

[6-(2-Fluoro-4-nitrophenoxy)pyrimidine-4-yl]carbamino acid phenyl ester (200 mg) is dissolved in tetrahydrofuran (16 ml), then added with stirring 1-methyl-4-(methylamino)piperidine (0,236 ml) and stirring is continued for 20 minutes the Reaction mixture is distributed between ethyl acetate (30 ml) and the us is placed in an aqueous solution of sodium hydrogen carbonate (20 ml). The organic layer was washed with saturated aqueous sodium hydrogen carbonate (20 ml), water (20 ml) and saturated saline (20 ml) in this order, then dried over anhydrous sodium sulfate. The solvent is evaporated, receiving untreated (218 mg), 3-[6-(2-fluoro-4-nitrophenoxy)pyrimidine-4-yl]-1-methyl-1-(1-methylpiperidin-4-yl)urea. The crude product (218 mg) was dissolved in methanol (5 ml) - tetrahydrofuran (5 ml), then add 10% palladium on coal (115 mg) in a nitrogen atmosphere, after which the nitrogen in the system is replaced with hydrogen and stirred for 3 hours. The catalyst removed from the reaction mixture by filtration and washed with ethanol. The filtrate is concentrated under reduced pressure, obtaining a residue, which is then suspended in a mixture of diethyl ether (2 ml) - hexane (4 ml). The solid is filtered off, dried in a stream of air, which is specified in the header connection (91,0 mg, 45%) as yellow powder.

Range1H-NMR (CDCl3) δ (ppm): 1.56 to around 1.74 (2H, m), of 1.80 (2H, DDD, J=3,6, 12, and 12.4 Hz), 2,07 (2H, m), is 2.30 (3H, c), 2,86-of 3.00 (5H, m), 3,74 (2H, Sirs), 4,18 (1H, m), 6,45 (1H, m), 6,51 (1H, m), 6,98 (1H, m), 7,29 (1H, Sirs), to 7.61 (1H, m), a 8.34 (1H, m).

ESI-MS (m/z): 375 [M+H]+.

Example of getting 107

4-Amino-3-terfenol

To a solution of 3-fluoro-4-NITROPHENOL (20 g) in a mixture of ethanol (200 ml) - tetrahydrofuran (125 ml) is added 10% palladium on coal (6.0 g) with subsequent paramasivan is eaten in an atmosphere of hydrogen at room temperature for 4.5 hours. The catalyst is removed from the mixture by filtration and washed with ethanol. The filtrate is concentrated under reduced pressure, obtaining mentioned in the title compound (16.1 g, 100%) as a solid pale yellow color.

Range1H-NMR (DMSO-d6) δ (ppm): to 4.38 (2H, m), 6,34 (1H, m), to 6.43 (1H, m), 6,59 (1H, DD, J=8,4, 10.4 Hz), 8,78 (1H, c).

Example of getting 108

4-(4-Amino-3-pertenece)pyridin-2-ylamine

Sodium hydride (1.1 g) is suspended in dimethyl sulfoxide (60 ml) in a stream of nitrogen, add at room temperature and with stirring 4-chloro-2-pyridylamine (2.9 g), described in WO 02/32872, and then 4-amino-3-terfenol (3.6 g, 28 mmol), then stirred in a stream of nitrogen at 150°C for 9 hours. The reaction mixture is cooled to room temperature and partitioned between 10% aqueous ammonia solution (150 ml) and ethyl acetate (350 ml). The organic layer is washed twice with 10% aqueous ammonia solution (150 ml). The combined aqueous layers again extracted with ethyl acetate (150 ml). The combined organic layer is washed twice with a saturated aqueous solution of sodium bicarbonate (100 ml) and dried over anhydrous sodium sulfate. The solvent is evaporated and get the remainder, which is purified column chromatography on silica gel (eluent: hexane:ethyl acetate = 1:1, ethyl acetate, then ethyl acetate:methanol = 10:1). The crude fraction containing the target link is, concentrate and get the remainder, which is purified column chromatography on silica gel (eluent: ethyl acetate). The fractions containing the target compound, concentrate, and get mentioned in the title compound (1.3 g, 26%) as a purple solid.

Range1H-NMR (DMSO-d6) δ (ppm): 5,11 (2H, c), USD 5.76 (1H, d, J=2.0 Hz), by 5.87 (2H, c)6,09 (1H, DD, J=2,0, 5.6 Hz), 6,69 (1H, m), to 6.80 (1H, DD, J=8,8, 10,0 Hz), to 6.88 (1H, DD, J=4,4, and 11.8 Hz), of 7.75 (1H, d, J=5.6 Hz).

ESI-MS (m/z): 220 [M+H]+.

Example of getting 109

Morpholine-4-carboxylic acid [4-(4-amino-3-pertenece)pyridine-2-yl]amide

To a solution of 4-(4-amino-3-pertenece)pyridine-2-ylamine (500 mg) in tetrahydrofuran (23 ml), add triethylamine (0,318 ml) and then add phenylcarbamate (0,357 ml, 2.28 mmol) under stirring and cooling in a bath with ice, and then stirred in nitrogen atmosphere for 1 hour and 20 minutes, the Reaction mixture was concentrated under reduced pressure, obtaining a residue, to which is added N,N-dimethylformamide (20 ml) and morpholine (0,994 ml) followed by stirring at room temperature for 8 hours. The reaction mixture is distributed between ethyl acetate (100 ml) and water (100 ml). The organic layer was washed with saturated aqueous sodium bicarbonate and dried over anhydrous sodium sulfate. The solvent is evaporated and get the remainder, which is purified column chromatography the raffia on silica gel (eluent: hexane:ethyl acetate = 1:1, the ethyl acetate, then ethyl acetate:methanol = 10:1). The obtained solid is suspended in a mixture of ethyl acetate:diethyl ether (1:10), filtered, washed with diethyl ether, and dried in a stream of air, getting mentioned in the title compound (48 mg, 6.3 per cent) in the form of a powder pale red color.

Range1H-NMR (DMSO-d6) δ (ppm): 3.40 in (4H, m), 3,55 (4H, m), 5,16 (2H, m), 6,53 (1H, DD, J=2,4, 5.8 Hz), 6,74 (1H, DDD, J=2,4, and 9.4, 9.4 Hz), PC 6.82 (1H, DD, J=9,4, and 9.4 Hz), 6,93 (1H, DD, J=2,4, 12.0 Hz), 7,32 (1H, d, J=2.4 Hz), 8,07 (1H, d, J=5.8 Hz), 9,19 (1H, c).

An example of retrieving 110

Pyrrolidin-1-carboxylic acid [4-(4-amino-3-pertenece)pyridine-2-yl]amide

To a solution of 4-(4-amino-3-pertenece)pyridine-2-ylamine (500 mg) in tetrahydrofuran (10 ml), add triethylamine (0,223 ml) and then with stirring and cooling in a bath with ice add phenylcarbamate (0,200 ml), then stirred under nitrogen atmosphere for 2 hours. The reaction mixture was concentrated under reduced pressure, obtaining a residue, to which is added N,N-dimethylformamide (10 ml) and pyrrolidine (0,667 ml) and stirred at room temperature for 21 hours. The reaction mixture is distributed between ethyl acetate (100 ml) and water (100 ml). The organic layer was washed with saturated saline and dried over anhydrous sodium sulfate. The solvent is evaporated and get the remainder, which is purified column chromatography on silica gel(eluent: hexane:ethyl acetate = 1:2, the ethyl acetate, then ethyl acetate:methanol = 10:1). The fractions containing the target compound, concentrate, and get mentioned in the title compound (94 mg, 13%) as a purple oil.

Range1H-NMR (DMSO-d6) δ (ppm): 1,80 (4H, m), and 3.31 (4H, m), 5,15 (2H, m), 6,51 (1H, DD, J=2,4, 5.8 Hz), 6,72 (1H, DD, J=2,2, 8,8 Hz), for 6.81 (1H, m), 6,92 (1H, DD, J=2,2, 12.0 Hz), 7,42 (1H, d, J=2.4 Hz), with 8.05 (1H, d, J=5,8 Hz), 8,61 (1H, c).

Example of getting 111

Methyl 4-chloropyridine-2-carboxylate

Thionyl chloride (500 ml) was stirred at room temperature and then gradually add pikolinos acid (200 g). In nitrogen atmosphere, the reaction mixture was stirred at 85°C for 20 min and at 100°C for a further 157 hours. The reaction mixture is cooled to room temperature and thionyl chloride evaporated under reduced pressure. To the obtained residue, slowly add methanol (500 ml), cooling in a bath with ice and then stirred for 1 hour in a bath with ice and then at room temperature for 17.5 hours. The reaction mixture was concentrated under reduced pressure, obtaining a residue, which is then partitioned between a mixture of ethyl acetate:tetrahydrofuran = 2:1 (1,0 l) and 1 N. aqueous sodium hydroxide solution (500 ml). The aqueous layer was extracted twice with ethyl acetate (500 ml). The combined organic layer was washed with saturated brine (500 ml) and dried over anhydrous sulfate NAT the Oia. The solvent is evaporated, obtaining a residue, to which is added hexane (200 ml) and diethyl ether (40 ml) and stirred at room temperature for 13 hours. The precipitated solid is filtered off, washed twice with a mixture of hexane (100 ml) and diethyl ether (20 ml) and dried in a stream of air, getting mentioned in the title compound (182 mg, 65.2 percent).

Range1H-NMR (DMSO-d6) δ (ppm): 3,99 (3H, c), 7,83 (1H, DD, J=2.0 a, 5,2 Hz), of 8.09 (1H, d, J=2.0 Hz), to 8.70 (1H, d, J=5,2 Hz).

Example of getting 112

Methyl 4-(3-fluoro-4-nitrophenoxy)pyridine-2-carboxylate

A mixture of methyl 4-chloropyridine-2-carboxylate (200 mg), 3-fluoro-4-NITROPHENOL (202 mg) and chlorobenzene (0.6 ml) is stirred under nitrogen atmosphere at 120°C within 2 hours and 20 minutes, the Reaction mixture was cooled to room temperature, receiving utverzhdennuyu the reaction mixture, which was then dissolved in a small amount of N,N-dimethylformamide and subjected to column chromatography on silica gel (eluent: hexane:ethyl acetate = 1:2, ethyl acetate, then ethyl acetate:methanol = 20:1 to 10:1). The fractions containing the target compound, concentrate, and get mentioned in the title compound (94 mg, 27.5 per cent) in the form of a solid pale yellow color.

Range1H-NMR (DMSO-d6) δ (ppm): to 3.89 (3H, c), 7,25 (1H, m), 7,45 (1H, DD, J=1,6, 5.6 Hz), 7,58 (1H, m), 7,71 (1H, d, J=1.6 Hz), 8,29 (1H, m), 8,72 (1H, d, J=5.6 Hz).

Example of getting 113

ethyl 4-(4-amino-3-pertenece)pyridine-2-carboxylate

To a solution of methyl 4-(3-fluoro-4-nitrophenoxy)pyridine-2-carboxylate (200 mg) in methanol (40 ml) is added 10% palladium on coal, followed by stirring in an atmosphere of hydrogen at room temperature for 4.5 hours. The catalyst removed from the reaction mixture by filtration and washed with methanol. The filtrate is concentrated under reduced pressure, obtaining a residue, which is purified column chromatography on silica gel (eluent: ethyl acetate). The fractions containing the target compound, concentrate, and get mentioned in the title compound in crude form (181 mg) as a brown oil.

Range1H-NMR (CDCl3) δ (ppm): 3,98 (3H, c), of 6.71 (1H, m), 6,78-6,85 (2H, m), 6,98 (1H, DD, J=2,4, 5,6 Hz), to 7.61 (1H, d, J=2.4 Hz), 8,56 (1H, d, J=5.6 Hz).

Example of getting 114

Methyl 4-{3-fluoro-4-[2-(4-tortenelmebol)atsetamino]phenoxy}pyridine-2-carboxylate

To a solution of methyl 4-(4-amino-3-pertenece)pyridine-2-carboxylate (179 mg) in N,N-dimethylformamide (2.0 ml) is added N-(4-forfinal)malonic acid (202 mg, of 1.02 mmol), and hexaphosphate benzotriazol-1-yloxytris(dimethylamino)phosphonium (453 mg, of 1.02 mmol), followed by stirring under nitrogen atmosphere at room temperature for 21 hours. The reaction mixture is distributed between ethyl acetate (100 ml) and saturated saline (50 ml). The organic layer was washed with saturated aqueous g is drocarbons sodium and saturated saline in this order, then dried over anhydrous sodium sulfate. The solvent is evaporated and get the remainder, which is purified column chromatography on silica gel (eluent: ethyl acetate, then ethyl acetate:methanol = 20:1). The fractions containing the target compound, concentrate, and get a solid substance that is suspended in diethyl ether, filtered and dried in a stream of air, getting mentioned in the title compound (96,3 mg, 31.9%) in the form of a powder purple-brown color.

Range1H-NMR (DMSO-d6) δ (ppm): 3,59 (2H, c), 3,86 (3H, c), 7,10 (1H, d, J=8,8 Hz), 7,17 (2H, m), 7,25 (1H, DD, J=2,4, 5,6 Hz), was 7.36 (1H, m), 7,49 (1H, d, J=2.4 Hz), 7,63 (1H, d, J=5,0, 8,8 Hz), of 8.09 (1H, m), 8,61 (1H, d, J=5.6 Hz), 10,14 (1H, c), 10,26 (1H, c).

Example of getting 115

4-{3-Fluoro-4-[2-(4-tortenelmebol)atsetamino]phenoxy}pyridine-2-carboxylic acid

To a solution of methyl 4-{3-fluoro-4-[2-(4-tortenelmebol)atsetamino]phenoxy}pyridine-2-carboxylate (96,3 mg) in ethanol (2.0 ml) is added water (0,50 ml) and the monohydrate of lithium hydroxide (15.7 mg), followed by stirring at room temperature for 4 hours. To the reaction mixture add 1 N. HCl (30 ml), then concentrated under reduced pressure. To the obtained residue is added a mixture of ethyl acetate (100 ml) - tetrahydrofuran (100 ml) and distribute the reaction mixture. The organic layer was washed with saturated saline and dried over anhydrous sodium sulfate. R is storytell evaporated and get a solid substance, which is then suspended in hexane, filtered and dried in a stream of air, getting mentioned in the title compound in crude form (99,5 mg) as a solid pale yellow color.

Range1H-NMR (DMSO-d6) δ (ppm): of 3.60 (2H, c), 7,08-7,11 (1H, m), 7,17 (2H, m), 7,25 (1H, DD, J=2,4, 5,6 Hz), 7,37(2H, DD, J=2,4, and 11.4 Hz), to 7.50 (1H, d, J=2.4 Hz), 7,63 (2H, DD, J=5,2, 9,2 Hz), of 8.09 (1H, m), at 8.60 (1H, d, J=5.6 Hz), 10,15 (1H, c), 10,27 (1H, c).

Example of getting 116-1

2-(Trimethylsilyl)ethyl (4-{3-fluoro-4-[2-(4-tortenelmebol)acetylamino]phenoxy}pyridine-2-yl)carbamate

Example of getting 116-2

N-[4-(2-Aminopyridine-4-yloxy)-2-forfinal]-N'-(4-forfinal)malonamide

To a solution of 4-{3-fluoro-4-[2-(4-tortenelmebol)atsetamino]phenoxy}pyridine-2-carboxylic acid (93,2 mg, 0,218 mmol) in N,N-dimethylformamide (1.0 ml) is added triethylamine (0,0759 ml, 0,545 mmol) and 2-(trimethylsilyl)ethanol (0,0344 ml, 0,240 mmol), then at room temperature add diphenylphosphinite (0,0517 ml, 0,240 mmol) and stirred under nitrogen atmosphere at room temperature for 30 min and at 110°C for 2 hours. The reaction mixture is cooled to room temperature and distributed between ethyl acetate (100 ml) and saturated aqueous sodium hydrogen carbonate (100 ml). The organic layer was washed with saturated saline and dried over anhydrous sodium sulfate. The solvent is evaporated and get the rest of imaut column chromatography on silica gel (Fuji Silysia NH, eluent: ethyl acetate, then ethyl acetate:methanol = 10:1)to give 2-(trimethylsilyl)ethyl (4-{3-fluoro-4-[2-(4-tortenelmebol)acetylamino]phenoxy}pyridine-2-yl)carbamate (example obtaining 116-1) (24,0 mg, 20.3%) and N-[4-(2-aminopyridine-4-yloxy)-2-forfinal]-N'-(4-forfinal)malonamide (example obtaining 116-2) (31,2 mg, 35,9%).

Example of getting 116-1

Range1H-NMR (CDCl3) δ (ppm): 0,02 (9H, c), 0,99-of 1.03 (2H, m)and 3.59 (2H, c), 4,18-to 4.23 (2H, m), 6,53 (1H, DD, J=1,6, 6,0 Hz), 6,86-of 6.90 (2H, m), 6,98 (2H, DD, J=4,4, 4,8 Hz), 7,51 (2H, DD, J=4,8, 8,8 Hz), 7,58 (1H, d, J=1,6 Hz)to 8.14 (1H, d, J=6.0 Hz), to 8.20 (1H, m), 9,07 (1H, Sirs), a 9.25 (1H, Sirs), 9,43 (1H, Sirs).

Example of getting 116-2

Range1H-NMR (CDCl3) δ (ppm): 3,61 (2H, c)and 4.65 (2H, Sirs), 5,95 (1H, d, J=2.2 Hz), of 6.26 (1H, DD, J=2,2, 6,0 Hz), 6,29-to 6.88 (2H, m), 6,97-7,02 (2H, m), 7,49 (2H, m), of 7.90 (1H, d, J=6.0 Hz), to 8.12 (1H, DD, J=9,0, 9.0 Hz), 9,34 (1H, c), 9,49 (1H, c).

Below is described the method of synthesis, the alternative shown in the example of obtaining 116-2.

To a solution of 4-(4-amino-3-pertenece)pyridine-2-ylamine (100 mg) in N,N-dimethylformamide (2.0 ml) is added N-(4-forfinal)malonic acid (189 mg), and hexaphosphate benzotriazol-1-yloxytris(dimethylamino)phosphonium (424 mg), followed by stirring at room temperature. The reaction mixture is distributed between ethyl acetate (100 ml) and saturated brine (80 ml). The aqueous layer was extracted with ethyl acetate (50 ml). The combined organic layer was washed with saturated aqueous solution of hydrocar is onata sodium and saturated saline solution, then dried over anhydrous sodium sulfate. The solvent is evaporated and get the remainder, which is purified column chromatography on silica gel (eluent: ethyl acetate ethyl acetate:methanol = 10:1). The fractions containing the target compound, concentrate, and get mentioned in the title compound (182 mg, 66,1%) as brown crystals.

Example of getting 117

Methyl 4-(4-benzyloxycarbonylamino-3-forfinal)pyridine-2-carboxylate

To a solution of methyl 4-(3-fluoro-4-nitrophenoxy)pyridine-2-carboxylate (851 mg) in tetrahydrofuran (200 ml) is added palladium hydroxide (309 mg, palladium content 20%), followed by stirring in an atmosphere of hydrogen at room temperature for 2.5 hours. The mixture is filtered to remove the catalyst, washed with tetrahydrofuran and concentrated under reduced pressure until the volume of liquid will be approximately 20 ml. of water is Added (15 ml), acetone (30 ml) and sodium carbonate (771 mg), then stirred in a bath with ice. Add dropwise benzyloxycarbonylamino (0,449 ml) and stirred at room temperature for 4 hours. The reaction mixture was concentrated under reduced pressure, obtaining a residue, which is then distributed between ethyl acetate (200 ml) and saturated saline (100 ml). The aqueous layer was extracted with ethyl acetate (50 ml×2). United agencies is practical layer was washed with saturated saline and dried over anhydrous sodium sulfate. The solvent is evaporated and get the remainder, which is purified column chromatography on silica gel (eluent: heptane:ethyl acetate = 1:2, then ethyl acetate). The fractions containing the target compound, concentrate, and get mentioned in the title compound (738 mg, 64%) as crystals pale yellow color.

Range1H-NMR (CDCl3) δ (ppm): 3,98 (3H, c), of 5.24 (2H, c), 6,87-6,93 (2H, m), of 6.99 (1H, m), 7,01 (1H, DD, J=2,4, a 5.4 Hz), of 7.36-7,44 (5H, m), 6,40 (1H, d, J=2.4 Hz), to 8.20 (1H, m), 8,59 (1H, d, J=5.4 Hz).

ESI-MS (m/z): 397 [M+H]+, 419 [M+Na]+.

Example of getting 118

4-(4-Benzyloxycarbonylamino-3-forfinal)pyridine-2-carboxylic acid

Methyl 4-(4-benzyloxycarbonylamino-3-forfinal)pyridine-2-carboxylate (1,02 g) dissolved in a mixture of ethanol (25 ml), methanol (50 ml) and N,N-dimethylformamide (7.5 ml), then add water (7.5 ml). At room temperature and with stirring, add the monohydrate of lithium hydroxide (185 mg) and continue stirring at room temperature for 1.5 hours. To the reaction mixture add 1 N. HCl (30 ml) and concentrate under reduced pressure. To the obtained residue, add a mixture of ethyl acetate (100 ml) and tetrahydrofuran (100 ml) and distribute the reaction mixture. The organic layer was washed with saturated saline (50 ml×3) and dried over anhydrous sodium sulfate. The solvent is evaporated and get a solid substance, which is eaten suspended in a mixture of diethyl ether (20 ml) and hexane (20 ml), filtered and dried in a stream of air, getting mentioned in the title compound (846 mg, 86,1%) as a solid pale brown color.

Range1H-NMR (DMSO-d6) δ (ppm): 5,18 (2H, c), was 7.08 (1H, m), 7.23 percent (1H, m), 7.24 to 7,46 (8H, m), of 7.75 (1H, m), 8,59 (1H, d, J=5.6 Hz), 9,59 (1H, c).

Example of getting 119-1

Benzyl [4-(2-aminopyridine-4-yloxy)-2-forfinal]carbamate

Example of getting 119-2

2-(Trimethylsilyl)ethyl [4-(4-benzyloxycarbonylamino-3-pertenece)pyridine-2-yl]carbamate

To a solution of 4-(4-benzyloxycarbonylamino-3-forfinal)pyridine-2-carboxylic acid (2.85 g) in N-organic (30 ml), add triethylamine (2,59 ml) and 2-(trimethylsilyl)ethanol (1,28 ml), then add diphenylphosphinite (2,59 ml) and stirred under nitrogen atmosphere at room temperature for 1 hour and at 90°C for 2 hours. The reaction mixture is cooled to room temperature and distributed between ethyl acetate (100 ml) and saturated aqueous sodium hydrogen carbonate (100 ml). The organic layer was washed with saturated saline solution. The solvent is evaporated and get the remainder, which is purified column chromatography on silica gel (eluent: heptane:ethyl acetate = 1:1 to 1:2, ethyl acetate, then ethyl acetate:methanol = 20:1 to 10:1). The fractions containing the two respective target compound, concentrate, receiving, respectively, 2-(trimethylsilyl)ethyl[4-(4-benzyloxycarbonylamino-3-pertenece)pyridine-2-yl]carbamate (example obtaining 119-2: 747 mg, 20,2%) as a solid yellow color and benzyl [4-(2-aminopyridine-4-yloxy)-2-forfinal]carbamate (example obtaining 119-1: 618 mg, 23,5%) as a solid brown color.

Example of getting 119-2

Range1H-NMR (CDCl3) δ (ppm): 0,06 (9H, m)of 1.03 (2H, m), 4,24 (2H, m), 5,23 (2H, c), is 6.54 (1H, DD, J=2,0, 5.6 Hz), 6,59-only 6.64 (1H, m), 6,66-6,93 (3H, m), 7,34-7,42 (5H, m), to 7.61 (1H, m), 8,10 (1H, d, J=5.6 Hz), 8,15 (1H, m).

ESI-MS: 520 [M+Na]+.

Example of getting 119-1

Range1H-NMR (CDCl3) δ (ppm): 4,49 (2H, m), 5,23 (2H, c), 5,95 (1H, d, J=2.0 Hz), of 6.26 (1H, DD, J=2.0 a, 6,0 Hz), 6,84-of 6.90 (2H, m), 7,00 (1H, m), 7,34-7,42 (5H, m), 7,94 (1H, d, J=6.0 Hz), 8,10 (1H, m).

ESI-MS: 354 [M+H]+.

Example obtain 120

Benzyl {4-[2-(3,3-dimethylurea)pyridine-4-yloxy]-2-forfinal}carbamate

To a solution of benzyl [4-(2-aminopyridine-4-yloxy)-2-forfinal]carbamate (163 mg, 0,461 mmol) in tetrahydrofuran (4,50 ml), add triethylamine (0,128 ml, 0,918 mmol), then added dropwise to phenylcarbamate (0,0872 ml, 0,695 mmol) and stirred at room temperature for 10 minutes, the Reaction mixture was concentrated under reduced pressure, obtaining a residue, to which is added N,N-dimethylformamide (2.0 ml), dimethylamine hydrochloride (188 mg, 2,31 mmol) and triethylamine (0,386 ml) followed by stirring at room temperature for 8 hours. The reaction mixture is distributed between ethyl acetate (50 ml) and water (30 ml). The organic layer is washed feast upon the authorized saline solution (30 ml× 3) and dried over anhydrous sodium sulfate. The solvent is evaporated and get the remainder, which is purified column chromatography on silica gel (eluent: ethyl acetate, then ethyl acetate:methanol = 20:1), obtaining mentioned in the title compound (165 mg, 47.5 per cent) in the form of a powder pale yellow color.

Range1H-NMR (CDCl3) δ (ppm): to 3.02 (6H, c), with 5.22 (2H, c), 6,51 (1H, DD, J=2.0 a, 6,0 Hz), 6.87 in-6,90 (3H, m), 7,20 (1H, m), 7,25-7,42 (5H, m), 7,66 (1H, d, J=2.0 Hz), 8,03 (1H, d, J=6.0 Hz), 8,12 (1H, Sirs).

ESI-MS (m/z): 425 [M+H]+, 447 [M+Na]+.

Example of getting 121

1-[4-(2-Aminopyridine-4-yloxy)-2-forfinal]-3-[2-(4-forfinal)acetyl]thiourea

To a solution of 2-(trimethylsilyl)ethyl [4-(4-benzyloxycarbonylamino-3-pertenece)pyridine-2-yl]carbamate (222 mg) in tetrahydrofuran (7.0 ml) is added 10% palladium on coal (71,2 mg), followed by stirring in an atmosphere of hydrogen at room temperature for 25 hours. The catalyst removed from the reaction mixture by filtration and washed with methanol (5.0 ml). In another vessel placed 4-florfenicol acid (103 mg) and thionyl chloride (0,448 ml), stirred at 90°C for 30 min, and concentrated under reduced pressure. The resulting residue is dissolved in acetonitrile (5.0 ml), then add the potassium thiocyanate (130 mg, of 1.34 mmol) and stirred at 50°C for 1 hour. The reaction mixture was added to the filtrate and stirred at whom atoi temperature for 1 hour. To the reaction mixture are added ethyl acetate (50 ml) and saturated saline (30 ml) and distribute the mixture. The organic layer was washed with saturated saline (30 ml×3) and dried over anhydrous sodium sulfate. The solvent is evaporated, obtaining a residue which is dissolved in tetrahydrofuran (5.0 ml), then added a 1M solution of tetrabutylammonium fluoride in tetrahydrofuran (0,891 ml) and stirred at room temperature for 30 minutes, the Reaction mixture was concentrated, 1M add even a portion of a solution of tetrabutylammonium fluoride in tetrahydrofuran (0.1 ml) and stirred at room temperature for 30 minutes Again add a 1M solution of tetrabutylammonium fluoride in tetrahydrofuran (0.5 ml) and stirred at room temperature overnight. To the reaction mixture are added ethyl acetate (50 ml) and saturated saline (30 ml) and distribute the mixture. The organic layer was washed with saturated saline (30 ml×3) and dried over anhydrous sodium sulfate. The solvent is evaporated and get the remainder, which is purified column chromatography on silica gel (Fuji Silysia NH, eluent: heptane:ethyl acetate = 1:2, ethyl acetate, then ethyl acetate:methanol = 20:1 to 10:1)to give the target compound (75,4 mg, 43.5 per cent) in the form of oil pale yellow color.

Range1H-NMR (CDCl3) δ (ppm): to 3.73 (2H, c)to 4.52 (2H, m), of 6.02 (1H, DD, J=0,4, 2.0 Hz, of 6.31 (1H, DD, J=2,0, 5.8 Hz), 6,88-6,92 (2H, m), 7,08-7,13 (2H, m), 7,27-7,31 (2H, m), 7,98 (1H, DD, J=0,4, 5.8 Hz), compared to 8.26 (1H, m), 8,98 (1H, Sirs), 12,30 (1H, c).

ESI-MS (m/z): 415 [M+H]+.

Below is described the method of synthesis, the alternative shown in the example of getting 121.

4-Florfenicol acid (482 mg) was dissolved in thionyl chloride (1,09 ml) and stirred at 60°C for 1 hour. The reaction mixture is cooled to room temperature and thionyl chloride evaporated under reduced pressure, obtaining a residue which is subjected to azeotropic distillation with toluene. The resulting residue is dissolved in acetonitrile (34,2 ml), add potassium thiocyanate (607 mg) and stirred at 50°C for 1 hour. The reaction mixture is cooled to room temperature, add 4-(4-amino-3-pertenece)pyridin-2-ylamine (500 mg) and stirred at room temperature for 18 hours. The reaction mixture was partitioned between water (50 ml) and ethyl acetate (100 ml). The organic layer was washed with saturated saline and dried over anhydrous sodium sulfate. The solvent is evaporated and get the remainder, which is purified column chromatography on silica gel (Fuji Silysia NH, eluent: heptane:ethyl acetate = 1:2, ethyl acetate, then ethyl acetate:methanol = 10:1). The fractions containing the target compound, concentrate, and get raw (945 mg, crude substance: 42,9%) specified in the header of the connection is the form of a brown oil. To the crude product (220 mg) is added a mixture of ethanol (0.5 ml) - diethyl ether (2.5 ml)to precipitate crystals, which are then filtered, washed with diethyl ether and dried in a stream of air, getting mentioned in the title compound (42 mg) as crystals of a pale brown color.

Example of getting 122

1-[4-(2-Aminopyridine-4-yloxy)-2-forfinal]-3-phenylacetylamino

To a solution of 2-(trimethylsilyl)ethyl [4-(4-benzyloxycarbonylamino-3-pertenece)pyridine-2-yl]carbamate (200 mg) in tetrahydrofuran (20 ml) is added 10% palladium on coal (for 85.6 mg), followed by stirring in an atmosphere of hydrogen at room temperature for 25 hours. The catalyst removed from the reaction mixture by filtration and washed with tetrahydrofuran. The filtrate is concentrated to a volume of 20 ml. of a Solution of 2-phenylacetylide (0,0862 ml) in acetonitrile (10 ml) and potassium thiocyanate (117 mg) was placed in another vessel, stirred in nitrogen atmosphere at 60°C for 2 hours and cooled to room temperature. To the mixture obtained previously concentrated filtrate and stirred at room temperature for 2 hours. To the reaction mixture are added ethyl acetate (50 ml) and saturated saline (30 ml) and distribute the mixture. The organic layer was washed with saturated saline (30 ml×3) and dried over anhydrous sodium sulfate. Races shall foretell evaporated and get the remainder, which is purified column chromatography on silica gel (eluent: heptane:ethyl acetate = 1:1 to 1:2, then ethyl acetate)to give pale yellow oil (250 mg). Pale-yellow oil was dissolved in tetrahydrofuran (0,80 ml), then added a 1M solution of tetrabutylammonium fluoride in tetrahydrofuran (0,804 ml) and stirred at room temperature for 30 minutes Add another portion of 1M solution of tetrabutylammonium fluoride in tetrahydrofuran (0,804 ml) followed by stirring at room temperature for 30 minutes To the reaction mixture are added ethyl acetate (50 ml) and saturated saline (30 ml) and distribute the mixture. The organic layer was washed with saturated saline (30 ml×3) and dried over anhydrous sodium sulfate. The solvent is evaporated and get the remainder, which is purified column chromatography on silica gel (eluent: heptane:ethyl acetate = 1:1 to 1:2, ethyl acetate, then ethyl acetate:methanol = 10:1), obtaining specified in the header of the product (of 58.9 mg, 37%) as a colorless powder.

Range1H-NMR (CDCl3) δ (ppm): 3,75 (2H, c), a 4.83 (2H, Sirs), 6,00 (1H, d, J=2.4 Hz), 6,32 (1H, DD, J=2,4, 6,0 Hz), 6,88-6,93 (2H, m), 7,26 was 7.45 (5H, m), to 7.93 (1H, d, J=6.0 Hz), 8,25-8,29 (1H, m), 8,87 (1H, Sirs), 12,34 (1H, c).

ESI-MS (m/z): 397 [M+H]+.

Below is described the method of synthesis, the alternative shown in the example of getting 122.

To a solution of 2-phenylacetylide (0,378 ml, 3.00 mmol) is acetonitrile (30 ml) was added potassium thiocyanate (583 mg, 6,00 mmol) and stirred under nitrogen atmosphere at 50°C for 1.5 hours. The reaction mixture is cooled to room temperature, then add 4-(4-amino-3-pertenece)pyridin-2-ylamine (438 mg, 2.00 mmol) and stirred at room temperature for 13 hours. The reaction mixture was partitioned between water (50 ml) and ethyl acetate (100 ml). The organic layer was washed with saturated aqueous sodium bicarbonate and saturated saline in this order, then dried over anhydrous sodium sulfate. The solvent is evaporated and get the remainder, which is purified column chromatography on silica gel (Fuji Silysia NH, eluent: heptane:ethyl acetate = 1:1, ethyl acetate, then ethyl acetate:methanol = 10:1). The fractions containing the target compound, concentrate, and get mentioned in the title compound (271 mg, 34,2%) as a brown oil.

Example of getting 123

Benzyl (2-fluoro-4-{2-[3-methyl-3-(1-methylpiperidin-4-yl)ureido]pyridine-4-yloxy}phenyl)carbamate

To a solution of benzyl [4-(2-aminopyridine-4-yloxy)-2-forfinal]carbamate (200 mg) in tetrahydrofuran (5.0 ml) is added triethylamine (0,197 ml), then added dropwise to phenylcarbamate (0,107 ml) and stirred at room temperature for 10 minutes, the Reaction mixture was concentrated under reduced pressure, obtaining a residue, to which is added N,N-dimethylformamide (2,0 is l) and 1-methyl-4-(methylamino)piperidine (0,329 ml) followed by stirring at room temperature within 18 hours. To the reaction mixture are added ethyl acetate (50 ml) and water (30 ml) and distribute the mixture. The organic layer was washed with saturated saline (30 ml×3) and dried over anhydrous sodium sulfate. The solvent is evaporated and get the remainder, which is purified column chromatography on silica gel (FUJI Silysia NH, heptane:ethyl acetate = 1:2, ethyl acetate, then ethyl acetate:methanol = 20:1 to 10:1), obtaining mentioned in the title compound (117 mg, 40.7 per cent) in the form of a powder pale yellow color.

Range1H-NMR (CDCl3) δ (ppm): 1,63-to 1.67 (2H, m), 1,72-to 1.82 (2H, m), 2,04-2,11 (2H, m), 2,28 (3H, c), 2,88 of 2.92 (5H, m), 4,17 (1H, m), 5,23 (2H, c), of 6.52 (1H, DD, J=2,4, 6,0 Hz), 6,85-6,92 (3H, m), 7,22 (1H, m), 7,34-7,44 (5H, m), 7,68 (1H, d, J=2.4 Hz), with 8.05 (1H, d, J=6.0 Hz), 8,12 (1H, m).

ESI-MS (m/z): 508 [M+H]+, 530 [M+Na]+.

Example of getting 124

3-[4-(4-Amino-3-pertenece)pyridine-2-yl]-1-methyl-1-(1-methylpiperidin-4-yl)urea

To a solution of benzyl (2-fluoro-4-{2-[3-methyl-3-(1-methylpiperidin-4-yl)ureido]pyridine-4-yloxy}phenyl)carbamate (110 mg) in tetrahydrofuran (10 ml) is added 10% palladium on coal (46.2 mg) and stirred under hydrogen atmosphere at room temperature for 18 hours. The catalyst removed from the reaction mixture by filtration and washed with tetrahydrofuran. The filtrate is dried over anhydrous sodium sulfate and concentrated to a volume of 40 ml of getting solution of the target compound in tetrahydrofuran (40 ml) a solution of pale is altago color. The solution is used in the next stage, assuming that the reaction proceeds quantitatively.

ESI-MS (m/z): 374 [M+H]+, 396 [M+Na]+.

An example of retrieving 125

2-Amino-4-(4-nitrophenoxy)pyridine

2-Amino-4-chloropyridine (2.00 g) was dissolved in N-organic (31.8 ml), and then in an atmosphere of nitrogen added 4-NITROPHENOL (6,51 g) and N,N-diisopropylethylamine (15,9 ml) followed by stirring at 150°C for 3 days. The reaction mixture is cooled to room temperature and distributed between ethyl acetate and 1 N. aqueous sodium hydroxide solution (32 ml). The organic layer is washed with water and saturated saline in this order, then dried over anhydrous sodium sulfate. The solvent is evaporated under reduced pressure, obtaining a residue, which is purified column chromatography on silica gel (eluent: hexane:ethyl acetate = 1:2 to 1:5). The fractions containing the target compound are concentrated under reduced pressure, obtaining a residue, which is then dried in vacuum, obtaining mentioned in the title compound (764 mg, 21.2%) of in a solid brown color.

Range1H-NMR (CDCl3) δ (ppm): of 4.54 (2H, Sirs), 6,11 (1H, c), 6.35mm (1H, m), 7,17 (2H, m), with 8.05 (1H, d, J=5.6 Hz), of 8.27 (2H, m).

Example of getting 126

Pyrrolidin-1-carboxylic acid [4-(4-nitrophenoxy)pyridine-2-yl]amide

2-Amino-4-(4-nitrophenoxy)pyridine (490 mg) is dissolved is in tetrahydrofuran (10 ml) under nitrogen atmosphere, then add dropwise a triethylamine (0,886 ml) and phenylcarbamate (0,798 ml) followed by stirring for 20 minutes To the reaction mixture add pyrrolidine (1,42 ml) and stirred for 40 minutes, the Reaction mixture was distributed between ethyl acetate and saturated aqueous ammonium chloride. The organic layer was washed with saturated aqueous ammonium chloride, saturated aqueous sodium bicarbonate, water and saturated saline in this order, then dried over anhydrous sodium sulfate. The solvent is evaporated under reduced pressure, obtaining a residue, which is purified column chromatography on silica gel (eluent: hexane:ethyl acetate = 1:1 to 1:3). The fractions containing the target compound are concentrated under reduced pressure, obtaining a residue, which is then dried in vacuum, obtaining mentioned in the title compound (639 mg, 91,8%) as a solid brown color.

1H-NMR Spectrum (CDCl3) δ (ppm): 1,98 (4H, m), of 3.46 (4H, m), of 6.65 (1H, DD, J=2,4, 5,6 Hz), was 7.08 (1H, Sirs), 7,19 (2H, m), to 7.84 (1H, d, J=2.4 Hz), 8,16 (1H, d, J=5.6 Hz), of 8.28 (2H, m).

Example of getting 127

Pyrrolidin-1-carboxylic acid [4-(4-aminophenoxy)pyridine-2-yl]amide

Pyrrolidin-1-carboxylic acid [4-(4-nitrophenoxy)pyridine-2-yl]amide (636 mg) dissolved in a mixture of tetrahydrofuran (18 ml) - methanol (18 ml) and then add 10% pall is Dios coal (412 mg) in a nitrogen atmosphere, then the nitrogen in the system is replaced with hydrogen and stirred overnight. After replacing the nitrogen in the system, the catalyst removed from the reaction mixture by filtration and washed with methanol. The filtrate is concentrated under reduced pressure, obtaining a residue which is suspended in a mixture of diethyl ether (10 ml) - hexane (10 ml). The solid is filtered off and dried in vacuum, obtaining specified in the header connection (524,9 mg, 90.7 percent).

Range1H-NMR (CDCl3) δ (ppm): 1,95 (4H, m), 3,44 (4H, m)to 3.64 (2H, Sirs), 6,48 (1H, DD, J=2,4, 5,6 Hz), 6,69 (2H, m), 6.90 to (2H, m), to 6.95 (1H, m), 7,66 (1H, m), to 7.99 (1H, m).

Example of getting 128

3-[4-(4-Nitrophenoxy)pyridine-2-yl]-1,1-dimethyloxetane

2-Amino-4-(4-nitrophenoxy)pyridine (761 mg) dissolved in tetrahydrofuran (14 ml) under nitrogen atmosphere, then added dropwise a triethylamine (1,16 ml) and phenylcarbamate (1,05 ml), cooling in a bath containing ice water, and stirred for 30 minutes To the reaction mixture add 2 N. the solution of dimethylamine in methanol) (6,95 ml), followed by stirring overnight. The reaction mixture is distributed between ethyl acetate and saturated aqueous ammonium chloride. The organic layer was washed with saturated aqueous ammonium chloride, saturated aqueous sodium bicarbonate, water and saturated saline in this order, then dried over besod the first sodium sulfate. The solvent is evaporated under reduced pressure, obtaining a residue, which is purified column chromatography on silica gel (eluent: hexane:ethyl acetate = 1:1 to 1:5). The fractions containing the target compound are concentrated under reduced pressure, obtaining a residue, which is then dried in vacuum, obtaining mentioned in the title compound (609 mg, 72,5%) as a solid brown color.

Range1H-NMR (CDCl3) δ (ppm): 3,03 (6H, c), of 6.65 (1H, DD, J=2,4, 5,6 Hz), 7,19 (2H, m), 7,21 (1H, m), 7,80 (1H, d, J=2.4 Hz), 8,16 (1H, d, J=5.6 Hz), of 8.28 (2H, m).

Example of getting 129

3-[4-(4-Aminophenoxy)pyridine-2-yl]-1,1-dimethyloxetane

3-[4-(4-Nitrophenoxy)pyridine-2-yl]-1,1-dimethyloxetane (607 mg) dissolved in a mixture of tetrahydrofuran (20 ml) - methanol (20 ml), and then in a nitrogen atmosphere, add 10% palladium on coal (236 mg), after which the nitrogen in the system is replaced with hydrogen and stirred overnight. After replacing the nitrogen in the system, the catalyst removed from the reaction mixture by filtration and washed with methanol. The filtrate is concentrated under reduced pressure and get the remainder, which is dried in vacuum, obtaining specified in the header connection (529,5 mg, 96,7%).

Range1H-NMR (CDCl3) δ (ppm): a 3.01 (6H, m)to 3.64 (2H, Sirs), 6,48 (1H, DD, J=2.0 a, 6,0 Hz), 6,70 (2H, m), 6.90 to (2H, m), 7,11 (1H, Sirs), to 7.61 (1H, d, J=2.0 Hz), to 7.99 (1H, d, J=6.0 Hz).

An example of retrieving 130

[4-(4-Nitrophenoxy)pyridine-2-yl]carbamino the th acid phenyl ester

2-Amino-4-(4-nitrophenoxy)pyridine (600 mg) dissolved in tetrahydrofuran (12 ml) under nitrogen atmosphere, then added dropwise a triethylamine (1,09 ml) and phenylcarbamate (0,979 ml) followed by stirring for 20 minutes To the reaction mixture are added morpholine (1,81 ml) and stirred for 25 minutes, the Reaction mixture was distributed between ethyl acetate and saturated aqueous ammonium chloride. The organic layer was washed with saturated aqueous ammonium chloride, saturated aqueous sodium bicarbonate, water and saturated saline in this order, then dried over anhydrous sodium sulfate. The solvent is evaporated under reduced pressure, obtaining a residue, which is then suspended in diethyl ether. The solid is filtered off and dried in a stream of air, getting mentioned in the title compound (854 mg, 93,8%) as a solid brown color.

Range1H-NMR (CDCl3) δ (ppm): 6.73 x (1H, DD, J=2,4, 5,6 Hz), 7,14-7,24 (4H, m), 7,32-7,46 (3H, m), 7,71 (1H, d, J=2.0 Hz), of 8.27 (2H, m), 8,32 (1H, d, J=5.6 Hz), 9,07 (1H, Sirs).

Example of getting 131

Morpholine-4-carboxylic acid [4-(4-nitrophenoxy)pyridine-2-yl]amide

[4-(4-Nitrophenoxy)pyridine-2-yl]carbamino acid phenyl ester (250 mg) is dissolved in tetrahydrofuran (7 ml) under nitrogen atmosphere and then add morpholine (0,187 ml). The reaction mixture per mesilat over night at room temperature. Then to the reaction mixture are added morpholine (0,187 ml) and stirred for 2 hours and 15 minutes the Reaction mixture is heated to 50°C and stirred for 1 hour. The reaction mixture is distributed between ethyl acetate and saturated aqueous ammonium chloride. The organic layer was washed with saturated aqueous ammonium chloride, water and saturated saline in this order, then dried over anhydrous sodium sulfate. The solvent is evaporated under reduced pressure, obtaining a residue, which is purified column chromatography on silica gel (eluent: hexane:ethyl acetate = 1:1 to 1:5). The fractions containing the target compound are concentrated under reduced pressure and get the remainder, which is then dried in vacuum, obtaining mentioned in the title compound (152 mg, 61.9%) in a solid brown color.

Range1H-NMR (CDCl3) δ (ppm): to 3.49 (4H, m), of 3.73 (4H, m), of 6.66 (1H, DD, J=2,4, 5,6 Hz), 7,19 (1H, m), 7,21 (1H, m), 7,29 (1H, Sirs), of 7.75 (1H, m), 8,17 (1H, d, J=5.6 Hz), of 8.28 (1H, m), 8,30 (1H, m).

Example of getting 132

Morpholine-4-carboxylic acid [4-(4-aminophenoxy)pyridine-2-yl]amide

Morpholine-4-carboxylic acid [4-(4-nitrophenoxy)pyridine-2-yl]amide (227 mg) dissolved in a mixture of ethanol (10 ml) - water (2 ml), add electrolytic iron powder (150 mg) and ammonium chloride (300 mg), and then heated from the reverse was built in the a IR for 1 hour. The reaction mixture is cooled to room temperature, add a mixture of ethyl acetate-tetrahydrofuran (1:1) and stirred. The mixture is filtered through celite to remove insoluble substances, which is washed with ethyl acetate and water. The organic layer of the filtrate washed with water and saturated saline, then dried over anhydrous sodium sulfate. The solvent is evaporated under reduced pressure, obtaining a residue, which is purified column chromatography on silica gel (eluent: hexane:ethyl acetate = 1:5, then ethyl acetate). The fractions containing the target compound are concentrated under reduced pressure, obtaining a residue, which is then suspended in a mixture of diethyl ether (6 ml) - hexane (12 ml). The solid is filtered and dried in a stream of air, getting mentioned in the title compound (81,3 mg, 59.3%) were in the form of a solid pale yellow color.

Range1H-NMR (CDCl3) δ (ppm): 3,48 (4H, m), the 3.65 (2H, Sirs), 3,71 (4H, m), 6,44-6,56 (1H, m), of 6.71 (2H, d, J=8,8 Hz), make 6.90 (2H, d, J=8,8 Hz), 7,21 (1H, Sirs), EUR 7.57 (1H, Sirs), to 7.99 (1H, m).

Example of getting 133

4-(Pyrrolidin-1-yl)piperidine-1-carboxylic acid [4-(4-aminophenoxy)pyridine-2-yl]amide

[4-(4-Nitrophenoxy)pyridine-2-yl]carbamino acid phenyl ester (100 mg) dissolved in tetrahydrofuran (2 ml) under nitrogen atmosphere, add 4-(pyrrolidin-1-yl)piperidine (148 mg) and stirred for 50 Minregion mixture is distributed between ethyl acetate and saturated aqueous ammonium chloride. The organic layer was washed with saturated aqueous ammonium chloride, water and saturated saline in this order, then dried over anhydrous sodium sulfate. The solvent is evaporated under reduced pressure, obtaining a residue, which is purified column chromatography on silica gel (Fuji Silysia NH, eluent: hexane:ethyl acetate = 1:2 to 1:8). The solvent is evaporated under reduced pressure, obtaining a residue, which is then dried in vacuum, obtaining 4-(pyrrolidin-1-yl)piperidine-1-carboxylic acid [4-(4-nitrophenoxy)pyridine-2-yl]amide in crude form.

4-(Pyrrolidin-1-yl)piperidine-1-carboxylic acid [4-(4-nitrophenoxy)pyridine-2-yl]amide (117 mg) dissolved in a mixture of tetrahydrofuran (3 ml) - methanol (3 ml), add 10% palladium on coal (61 mg) in a nitrogen atmosphere, after which the nitrogen in the system is replaced with hydrogen and stirred overnight. After replacing the nitrogen in the system, the catalyst removed from the reaction mixture by filtration and washed with ethanol. The filtrate is concentrated under reduced pressure, obtaining a residue, which is then suspended in a mixture of diethyl ether (2 ml) - hexane (2 ml). The solid is filtered and dried in a stream of air, getting mentioned in the title compound (59,5 mg, 54.7 per cent).

Range1H-NMR (DMSO-d6) δ (ppm): 1,27 (2H, m)of 1.66 (4H, m), of 1.78 (2H, m), 2,11 (1H, m), 2,46 (4H, m), 2,85 (2H, m), of 3.96 (2H, m), 5,04-of 5.15 (2H, m), 6,46 (1H, DD, J=a 2.0, 5.6 Hz), 6,60 (2H, d, J=8,8 Hz), to 6.80 (2H, d, J=8,8 Hz), 7,29 (1H, d, J=2.0 Hz), 8,03 (1H, d, J=5.6 Hz), 9,06 (1H, Sirs).

Example of getting 134

4-(piperidine-1-yl)piperidine-1-carboxylic acid [4-(4-aminophenoxy)pyridine-2-yl]amide

[4-(4-Nitrophenoxy)pyridine-2-yl]carbamino acid phenyl ester (100 mg) dissolved in tetrahydrofuran (2 ml) under nitrogen atmosphere, add 4-(piperidine-1-yl)piperidine (144 mg) and stirred for 30 minutes, the Reaction mixture was distributed between ethyl acetate and saturated aqueous ammonium chloride. The organic layer was washed with saturated aqueous ammonium chloride, water and saturated saline in this order, then dried over anhydrous sodium sulfate. The solvent is evaporated under reduced pressure, obtaining a residue, which is purified column chromatography on silica gel (Fuji Silysia NH, eluent: hexane:ethyl acetate = 1:2 to 1:8). The solvent is evaporated under reduced pressure and get the remainder, which is then dried in vacuum, obtaining 4-(piperidine-1-yl)piperidine-1-carboxylic acid [4-(4-nitrophenoxy)pyridine-2-yl]amide in crude form.

4-(piperidine-1-yl)piperidine-1-carboxylic acid [4-(4-nitrophenoxy)pyridine-2-yl]amide (121 mg) dissolved in a mixture of tetrahydrofuran (3 ml) - methanol (3 ml), and then in a nitrogen atmosphere, add 10% palladium on coal (61 mg), after which the nitrogen in the system is replaced by hydrogen and peremeshivayte during the night. After replacing the nitrogen in the system, the catalyst removed from the reaction mixture by filtration and washed with ethanol. The filtrate is concentrated under reduced pressure, obtaining a residue, which is then suspended in a mixture of diethyl ether (2 ml) - hexane (2 ml). The solid is filtered off, dried in a stream of air, which is specified in the header connection (84,8 mg, 75.2 per cent).

Range1H-NMR (CDCl3) δ (ppm): 1,38-of 1.78 (8H, m)to 1.86 (2H, m), 2,38-of 2.54 (5H, m), 2,85 (2H, m), the 3.65 (2H, Sirs), of 4.12 (2H, m), 6.48 in (1H, DD, J=2,0, 5.6 Hz), 6,66-6,76 (2H, m), 6,86-6,94 (2H, m), 7,20 (1H, m), EUR 7.57 (1H, m), to 7.99 (1H, d, J=5.6 Hz).

Example of getting 135

3-[4-(4-Aminophenoxy)pyridine-2-yl]-1-methyl-1-(1-methylpiperidin-4-yl)urea

[4-(4-Nitrophenoxy)pyridine-2-yl]carbamino acid phenyl ester (150 mg) is dissolved in N,N-dimethylformamide (4 ml) under nitrogen atmosphere, then add N-methyl-N-(1-methylpiperidin-4-yl)amine (0,186 mg) and stirred for 1 hour. The reaction mixture is distributed between ethyl acetate (40 ml) and saturated aqueous ammonium chloride (10 ml). The organic layer was washed with saturated aqueous ammonium chloride, water and saturated saline in this order, then dried over anhydrous sodium sulfate. The solvent is evaporated under reduced pressure, obtaining a residue, which is purified column chromatography on silica gel (Fuji Silysia NH, eluent: heptane:ethyl acetate = 1:1 then ethyl acetate). The fractions containing the target compound are concentrated under reduced pressure, obtaining 3-[4-(4-nitrophenoxy)pyridine-2-yl]-1-methyl-1-(1-methylpiperidin-4-yl)urea (117,7 mg, 71,5%) in crude form.

3-[4-(4-Nitrophenoxy)pyridine-2-yl]-1-methyl-1-(1-methylpiperidin-4-yl)urea dissolved in a mixture of tetrahydrofuran (4 ml) - methanol (4 ml), and then in a nitrogen atmosphere, add 10% palladium on coal (65 mg), after which the nitrogen in the system is replaced with hydrogen and stirred overnight. After replacing the nitrogen in the system, the catalyst removed from the reaction mixture by filtration and washed with methanol. The filtrate is concentrated under reduced pressure, obtaining a residue, which is purified column chromatography on silica gel (Fuji Silysia NH, eluent: ethyl acetate). The fractions containing the target compound are concentrated under reduced pressure, obtaining specified in the header connection (113,5 mg, quantitative yield) as a colorless powder.

Range1H-NMR (CDCl3) δ (ppm): 1,25-1,32 (1H, m), 1.77 in (2H, m), of 2.08 (2H, m)to 2.29 (3H, c), 2,84-2,96 (6H, m), the 3.65 (2H, Sirs), 4,20 (1H, m), 6.48 in (1H, DD, J=2,4, 6,0 Hz), 6,70 (2H, m), 6.90 to (2H, m), 7,14 (1H, Sirs), a 7.62 (1H, m), of 8.00 (1H, d, J=6.0 Hz).

ESI-MS (m/z): 356 [M+H]+.

Example of getting 136

4-(4-Amino-2-pertenece)-2-[(4-hydroxypiperidine-1-yl)carbylamine]pyridine

4-(2-Fluoro-4-nitrophenoxy)-2-[(4-hydroxypiperidine-1-yl)carbylamine]pyridine (169 mg) dissolved in a mixture of meth is Nol (5 ml) - tetrahydrofuran (5 ml), and then in a nitrogen atmosphere, add 10% palladium on coal (200 mg), after which the nitrogen in the system is replaced with hydrogen and stirred for 2 hours. After replacing the nitrogen in the system, the catalyst removed from the reaction mixture by filtration and washed with ethyl acetate. The filtrate is concentrated under reduced pressure, obtaining mentioned in the title compound (168 mg, quantitative yield) in the form of a powder pale yellow color.

Range1H-NMR (CDCl3) δ (ppm): 1,40-1,70 (2H, m), 1,80-2,00 (2H, m), 3,10-3,30 (2H, m), 3,74 (2H, Sirs), of 3.80-4.00 points (3H, m), 6,40-6,55 (3H, m), 6.90 to-7,30 (2H, m), 7,58 (1H, c), 8,01 (1H, d, J=6.0 Hz).

Example of getting 137

Morpholine-4-carboxylic acid [4-(2-fluoro-4-nitrophenoxy)pyridine-2-yl]amide

To a solution of 4-(2-fluoro-4-nitrophenoxy)pyridine-2-ylamine (1,00 g) in tetrahydrofuran (50 ml), add triethylamine (1,12 ml) and phenylcarbamate (0,906 ml) under stirring and cooling in a bath with ice, followed by stirring in a bath with ice for 1 hour. The reaction mixture was concentrated under reduced pressure, obtaining a residue, to which is added N,N-dimethylformamide (16 ml) and morpholine (1.4 ml) followed by stirring at room temperature for 4.5 hours. The reaction mixture is distributed between ethyl acetate (150 ml) and water (100 ml). The organic layer was washed with 1 N. aqueous sodium hydroxide solution, saturated salt solution,1 N. HCl and saturated saline in this order, then dried over anhydrous sodium sulfate. The solvent is evaporated under reduced pressure and get solid, which is then suspended in diethyl ether (50 ml), filtered and dried in a stream of air, getting mentioned in the title compound (941 mg, 64.8 per cent) in the form of a powder pale yellow color.

Range1H-NMR (DMSO-d6) δ (ppm): 3,42 (4H, m), of 3.56 (4H, m), 6,77 (1H, DD, J=2,4, 5.8 Hz), 7,51 (1H, d, J=2.4 Hz), to 7.59 (1H, d, J=2.4 Hz), 8,19 (1H, m), 8,23 (1H, d, J=5.8 Hz), 8,43 (1H, DD, J=2,4, 10.4 Hz), 9,44 (1H, c).

Example of getting 138

Morpholine-4-carboxylic acid [4-(4-amino-2-pertenece)pyridine-2-yl]amide

To a suspension of morpholine-4-carboxylic acid [4-(2-fluoro-4-nitrophenoxy)pyridine-2-yl]amide (941 mg) in ethanol (50 ml) is added water (10 ml), electrolytic iron powder (581 mg), ammonium chloride (1,11 g) and N,N-dimethylformamide (0.75 ml) followed by stirring at 90°C for 30 minutes, the Reaction mixture was cooled to room temperature and filtered to remove insoluble substances, which are washed with water and N,N-dimethylformamide in the specified order. The filtrate is concentrated under reduced pressure, obtaining a residue, to which is added ethyl acetate (100 ml) and water (100 ml) and distribute the mixture. The aqueous layer was extracted with ethyl acetate. The combined organic layer was washed with water and saturated the output saline solution in this order, then dried over anhydrous sodium sulfate. The solvent is evaporated under reduced pressure, obtaining a residue, which is purified column chromatography on silica gel (Fuji Silysia NH, eluent: hexane:ethyl acetate = 1:1 to 1:2, ethyl acetate, then ethyl acetate:methanol = 20:1 to 10:1). The fractions containing the target compound, concentrate, and get mentioned in the title compound (759 mg, 87.8 per cent) in the form of oil pale yellow color.

Range1H-NMR (DMSO-d6) δ (ppm): 3.40 in (4H, m), 3,55 (4H, m), 5,44 (2H, m), 6,40 (1H, DD, J=2,4, and 8.4 Hz), of 6.49 (1H, DD, J=2,4, 13,0 Hz), is 6.54 (1H, DD, J=2,4, 5,6 Hz), to 6.95 (1H, m), 7,32 (1H, d, J=2.4 Hz), 8,07 (1H, d, J=5,6 Hz), 9,20 (1H, c).

Example of getting 139

3-[6-(2-Fluoro-4-nitrophenoxy)pyrimidine-4-yl]-1-(3-diethylaminopropyl)-1-metalmachine

6-(2-Fluoro-4-nitrophenoxy)pyrimidine-4-ylamine (50 mg) dissolved in tetrahydrofuran (2 ml) under nitrogen atmosphere, add triethylamine (0,0697 ml) and phenylcarbamate (0,0627 ml), cooling in a bath with ice, and stirred at room temperature for 30 minutes, the Reaction mixture was concentrated under reduced pressure, obtaining a residue, to which is added N,N-dimethylformamide (2 ml) and N,N-diethyl-N'-methylpropan-1,3-diamine (115 mg) followed by stirring at room temperature for 2 hours. The reaction mixture is distributed between ethyl acetate and saturated aqueous ammonium chloride. The organic layer is washed on Ishenim aqueous solution of ammonium chloride, water and saturated saline in this order, then dried over anhydrous sodium sulfate. The solvent is evaporated under reduced pressure, obtaining a residue, which is purified column chromatography on silica gel (eluent: hexane:ethyl acetate = 2:1 to 1:1, then ethyl acetate:ethanol = 19:1). The fractions containing the target compound are concentrated under reduced pressure and get the remainder, which is then dried in vacuum, obtaining specified in the header connection (55.7 mg, 66,2%) as a solid yellow color.

Range1H-NMR (CDCl3) δ (ppm): 1,08 (6H, m), equal to 1.82 (2H, m), of 2.51 (2H, t, J=6.0 Hz), 2,68 (4H, q, J=7.2 Hz), to 2.94 (3H, c), is 3.41 (2H, t, J=6.0 Hz), 7,39 (1H, m), 7,56 (1H, c), 8,10 (2H, m), 8,29 (1H, c), 11,70 (1H, Sirs).

An example of retrieving 140

3-[6-(4-Amino-2-pertenece)pyrimidine-4-yl]-1-(3-diethylaminopropyl)-1-metalmachine

3-[6-(2-Fluoro-4-nitrophenoxy)pyrimidine-4-yl]-1-(3-diethylaminopropyl)-1-metalmachine (54,0 mg) dissolved in a mixture of tetrahydrofuran (2 ml) - methanol (2 ml), then add 10% palladium on coal to 27.2 mg), after which the nitrogen in the system is replaced with hydrogen and stirred overnight. After replacing the nitrogen in the system, the catalyst removed from the reaction mixture by filtration and washed with methanol. The filtrate is concentrated under reduced pressure, obtaining a residue, which is purified column chromatography on silica gel (Fuji Silysia NH, eluent: hexane:this is the acetate = 1:1, then ethyl acetate). The fractions containing the target compound are concentrated under reduced pressure, obtaining specified in the header connection (to 34.3 mg, 68,6%) as a solid pale yellow color.

Range1H-NMR (CDCl3) δ (ppm)with 1.07 (6H, t, J=7.2 Hz), to 1.79 (2H, m), 2.49 USD (2H, t, J=6 Hz), to 2.67 (4H, q, J=7.2 Hz), 2.91 in (3H, m), 3,39 (2H, m), 3,70 (2H, Sirs), of 6.45 (1H, m), of 6.49 (1H, DD, J=2,4, and 11.6 Hz), 6,97 (1H, m), 7,20-7,30 (1H, m), 7,40 (1H, m), with 8.33 (1H, m).

ESI-MS m/z:391 [M+H]+

Example of getting 141

Benzyl (2-fluoro-4-{2-[(4-pyrrolidin-1-reparacin-1-carbonyl)amino]pyridine-4-yloxy}phenyl)carbamate

To a solution of benzyl [4-(2-aminopyridine-4-yloxy)-2-forfinal]carbamate (230 mg) in tetrahydrofuran (6,50 ml), add triethylamine (0,181 ml), then added dropwise to phenylcarbamate (0,123 ml) under stirring and cooling in a bath with ice, followed by stirring for 10 minutes the Reaction mixture was concentrated under reduced pressure, obtaining a residue, to which is added N,N-dimethylformamide (2.0 ml) and 4-(1-pyrrolidinyl)piperidine (301 mg), followed by stirring at room temperature for 11 hours. To the reaction mixture are added ethyl acetate (50 ml) and water (30 ml) and distribute the mixture. The organic layer was washed with saturated saline (30 ml×3) and dried over anhydrous sodium sulfate. The solvent is evaporated under reduced pressure and get the rest of imaut column chromatography on silica gel (FUJI Silysia NH, eluent: heptane:ethyl acetate = 1:2, ethyl acetate, then ethyl acetate:methanol = 10:1), obtaining mentioned in the title compound (165 mg, 47.5 per cent) in the form of a powder pale yellow color.

Range1H-NMR (CDCl3) δ (ppm): 1,27 (2H, m), 1,47-of 1.56 (2H, m)of 1.93 (4H, m), of 2.20 (1H, m), 2.57 m (4H, m)of 3.00 (2H, m), was 4.02 (2H, m), 5,23 (2H, c), of 6.50 (1H, DD, J=2,0, 5.6 Hz), 6,85-6,91 (3H, m), 7,34-7,44 (5H, m), 7,62 (1H, d, J=2.0 Hz), of 8.04 (1H, d, J=5.6 Hz), 8,12 (1H, Sirs).

ESI-MS (m/z): 534 [M+H]+.

Example of getting 142

4-(Pyrrolidin-1-yl)piperidine-1-carboxylic acid [4-(4-amino-3-pertenece)pyridine-2-yl]amide

To a solution of benzyl (2-fluoro-4-{2-[(4-pyrrolidin-1-reparacin-1-carbonyl)amino]pyridine-4-yloxy}phenyl)carbamate (91 mg) in tetrahydrofuran (10 ml) is added 10% palladium on coal cases (36.4 mg) and stirred under hydrogen atmosphere at room temperature for 3.5 hours. Add ethanol (5.0 ml) and stirred under hydrogen atmosphere at room temperature for 1.5 hours. The reaction mixture is filtered to remove the catalyst and washed with a small amount of tetrahydrofuran, getting the solution specified in the title compound in tetrahydrofuran. The solution is concentrated almost to dryness and then used in the following stage without further purification.

ESI-MS (m/z: 400 [M+H]+.

Example 1

Pyrrolidin-1-carboxylic acid {6-[2-fluoro-4-(3-phenylacetylamino)phenoxy]pyrimidine-4-yl}amide

2-Phenylacetylene (0079 ml) dissolved in acetonitrile (3 ml) under nitrogen atmosphere, add potassium thiocyanate (116,6 mg) at 60°C and stirred at the same temperature for 2 hours. The reaction mixture is cooled to room temperature, then add a solution of 4-(4-amino-2-pertenece)-6-[(pyrrolidin-1-yl)carbylamine]pyrimidine (76,0 mg) in acetonitrile (3 ml) and stirred for 1 hour. The reaction mixture is distributed between ethyl acetate and saturated aqueous sodium bicarbonate. The organic layer was washed with saturated aqueous sodium bicarbonate, water and saturated saline in this order, then dried over anhydrous sodium sulfate. The solvent is evaporated under reduced pressure, obtaining a residue, which is purified column chromatography on silica gel (eluent: hexane:ethyl acetate = 1:4). The fractions containing the target compound, concentrate, and get the remainder, which is suspended in a mixture of diethyl ether (3 ml) - hexane (3 ml). The solid is filtered and dried in a stream of air, getting mentioned in the title compound (58,3 mg, 45.3 per cent) in the form of white powder.

Range1H-NMR (CDCl3) δ (ppm): 2,00 (4H, m), 3,49 (4H, m), 3,74 (2H, c), 7,42-to 7.50 (8H, m), 7,71 (1H, m), 7,86 (1H, DD, J=2,8, and 11.6 Hz), 8,83 (1H, m), 8,51 (1H, m), 12,43 (1H, c).

Example 2

Morpholine-4-carboxylic acid {6-[2-fluoro-4-(3-phenylacetylamino)phenoxy]pyrimidine-4-yl}amide

2-Phenylacetylene (0,064 ml) dissolve the in acetonitrile (3 ml) under nitrogen atmosphere, then add the potassium thiocyanate (94,8 mg) at 60°C and stirred at the same temperature for 2 hours. The reaction mixture is cooled to room temperature, add a solution of morpholine-4-carboxylic acid [6-(4-amino-2-pertenece)pyrimidine-4-yl}amide (65,0 mg) in acetonitrile (3 ml) and stirred for 1 hour. The reaction mixture is distributed between ethyl acetate and saturated aqueous sodium bicarbonate. The organic layer was washed with saturated aqueous sodium bicarbonate, water and saturated saline in this order, then dried over anhydrous sodium sulfate. The solvent is evaporated under reduced pressure, obtaining a residue, which is purified column chromatography on silica gel (eluent: hexane:ethyl acetate = 1:4). The fractions containing the target compound, concentrate, and get the remainder, which is suspended in a mixture of diethyl ether (3 ml) - hexane (3 ml). The solid is filtered off, dried in a stream of air, which is specified in the header of the connection (of 54.4 mg, 54.6%) in the form of white powder.

Range1H-NMR (CDCl3) δ (ppm): of 3.53 (4H, m in), 3.75 (6H, m), 7,42-to 7.50 (8H, m), of 7.64 (1H, m), 7,86 (1H, DD, J=2,4, and 11.6 Hz), a 8.34 (1H, m), 8,51 (1H, m), to 12.44 (1H, c).

Example 3

Pyrrolidin-1-carboxylic acid [6-(2-fluoro-4-{3-[2-(4-forfinal)acetyl]touraid}phenoxy)pyrimidine-4-yl]amide

2-(4-Forfinal)acetyl arid (135 mg) was dissolved in acetonitrile (5 ml) under nitrogen atmosphere, then add the potassium thiocyanate (152 mg) at 60°C and stirred at the same temperature for 1.5 hours. The reaction mixture is cooled to room temperature, add a solution of 4-(4-amino-2-pertenece)-6-[(pyrrolidin-1-yl)carbylamine]pyrimidine (99,6 mg) in acetonitrile (3 ml) and stirred for 15 minutes, the Reaction mixture was distributed between ethyl acetate and saturated aqueous sodium bicarbonate. The organic layer was washed with saturated aqueous sodium bicarbonate, water and saturated saline in this order, then dried over anhydrous sodium sulfate. The solvent is evaporated under reduced pressure, obtaining a residue, which is purified column chromatography on silica gel (eluent: hexane:ethyl acetate = 1:3). The fractions containing the target compound, concentrate, and get the remainder, which is suspended in a mixture of diethyl ether (5 ml) - hexane (5 ml). The solid is filtered off, dried in a stream of air, which is specified in the header connection (111,8 mg, 69.5 per cent) in the form of a solid pale yellow color.

Range1H-NMR (DMSO-d6) δ (ppm): to 1.83 (4H, m)to 3.41 (4H, m), 3,83 (2H, m), 7,18 (2H, DD, J=8,8, 8,8 Hz), 7,46 is 7.50 (4H, m)to 7.50 (1H, c), 7,88 (1H, d, J=12,4 Hz), 8,40 (1H, c), 9,43 (1H, Sirs), to 11.79 (1H, Sirs), KZT 12.39 (1H, Sirs).

Example 4

Morpholine-4-carboxylic acid [6-[2-fluoro-4-{3-[2-(4-forfinal)acetyl]tiore is to}phenoxy)pyrimidine-4-yl]amide

2-(4-Forfinal)acetylchloride (103 mg) was dissolved in acetonitrile (3 ml) under nitrogen atmosphere, then adding potassium thiocyanate (116 mg) at 60°C and stirred at the same temperature for 2 hours. The reaction mixture is cooled to room temperature, add a solution of 4-(4-amino-2-pertenece)-6-[(morpholine-4-yl)carbylamine]pyrimidine (of 79.5 mg) in acetonitrile (3 ml) and stirred for 10 minutes, the Reaction mixture was distributed between ethyl acetate and saturated aqueous sodium bicarbonate. The organic layer was washed with saturated aqueous sodium bicarbonate, water and saturated saline in this order, then dried over anhydrous sodium sulfate. The solvent is evaporated under reduced pressure, obtaining a residue, which is purified column chromatography on silica gel (eluent: hexane:ethyl acetate = 1:3). The fractions containing the target compound, concentrate, and get the remainder, which is suspended in a mixture of diethyl ether (5 ml) - hexane (5 ml). The solid is filtered off, dried in a stream of air, which is specified in the header connection (71,9 mg, 56,9%) as a solid pale yellow color.

Range1H-NMR (CDCl3) δ (ppm): of 3.53 (4H, m), 3,71 (2H, m), of 3.75 (4H, m), 7,12 (2H, m), 7,22 (1H, m), 7,25-7,34 (2H, m), of 7.36 (1H, d, J=7,6 Hz), the 7.43 (1H, Sirs), the 7.65 (1H, c), 7,86 (1H, DD, J=2,4, and 11.6 Hz), a 8.34 (1H, c), to 8.57 (1H, Sirs), 12,40 1H, Sirs).

Example 5

Piperidine-1-carboxylic acid {6-[2-fluoro-4-(3-phenylacetylamino)phenoxy]pyrimidine-4-yl}amide

2-Phenylacetylene (0,068 ml) dissolved in acetonitrile (5 ml) under nitrogen atmosphere, then adding potassium thiocyanate (100 mg) at 60°C and stirred at the same temperature for 1.5 hours. The reaction mixture is cooled to room temperature, add a solution of piperidine-1-carboxylic acid [6-(4-amino-2-pertenece)pyrimidine-4-yl]amide (114 mg) in acetonitrile (3 ml) and stirred for 30 minutes, the Reaction mixture was distributed between ethyl acetate and saturated aqueous sodium bicarbonate. The organic layer was washed with saturated aqueous sodium bicarbonate, water and saturated saline in this order, then dried over anhydrous sodium sulfate. The solvent is evaporated under reduced pressure, obtaining a residue, which is purified column chromatography on silica gel (eluent: hexane:ethyl acetate = 1:1). The fractions containing the target compound, concentrate, and get the remainder, which is suspended in a mixture of diethyl ether (5 ml) - hexane (5 ml). The solid is filtered off, dried in a stream of air, which is specified in the header connection (88,8 mg, 50.8 per cent) in the form of a solid pale yellow color.

Range1H-NMR (CDCl3) δ (ppm): 1,54-1,74 (6, m)of 3.48 (4H, m), 3,74 (2H, c), 7,18 is 7.50 (8H, m), of 7.64 (1H, c), 7,86 (1H, DD, J=2,4, 11.2 Hz), with 8.33 (1H, c), and 8.50 (1H, Sirs), 12,43 (1H, Sirs).

Example 6

Piperidine-1-carboxylic acid [6-(2-fluoro-4-{3-[2-(4-forfinal)acetyl]touraid}phenoxy)pyrimidine-4-yl]amide

2-(4-Forfinal)acetylchloride (92 mg) was dissolved in acetonitrile (5 ml) under nitrogen atmosphere and then potassium thiocyanate (104 mg) is added at 60°C, followed by stirring at the same temperature for 1.5 hours. The reaction mixture is cooled to room temperature, add a solution of piperidine-1-carboxylic acid [6-(4-amino-2-pertenece)pyrimidine-4-yl]amide (118 mg) in acetonitrile (3 ml) and stirred for 30 minutes, the Reaction mixture was distributed between ethyl acetate and saturated aqueous sodium bicarbonate. The organic layer was washed with saturated aqueous sodium bicarbonate, water and saturated saline in this order, then dried over anhydrous sodium sulfate. The solvent is evaporated under reduced pressure, obtaining a residue, which is purified column chromatography on silica gel (Fuji Silysia NH, eluent: hexane:ethyl acetate = 1:1). The fractions containing the target compound, concentrate, and get the remainder, which is suspended in a mixture of diethyl ether (5 ml) - hexane (5 ml). The solid is filtered off, dried in a stream of air, which is specified in the header is EDINENIE (98,4 mg, 52,5%) as a solid pale yellow color.

Range1H-NMR (CDCl3) δ (ppm): 1,52-of 1.74 (6H, m), of 3.48 (4H, m), 3,71 (2H, c), 7,05-to 7.15 (2H, m), 7,22 (1H, m), 7,25-to 7.32 (2H, m), 7,35-7,45 (2H, m), of 7.64 (1H, c), 7,86 (1H, DD, J=2,8, and 11.6 Hz), with 8.33 (1H, c), 8,55 (1H, Sirs), KZT 12.39 (1H, Sirs).

Example 7

3-[6-(2-Fluoro-4-{3-[2-(4-forfinal)acetyl]touraid}phenoxy)pyrimidine-4-yl]-1,1-dimethyloxetane

2-(4-Forfinal)acetylchloride (148 mg) was dissolved in acetonitrile (5 ml) under nitrogen atmosphere, then adding potassium thiocyanate (104 mg) at 60°C and stirred at the same temperature for 5 hours. The reaction mixture is cooled to room temperature, add a solution of 1-[4-(4-amino-2-pertenece)pyrimidine-6-yl]-3-dimethyloxetane (100 mg) in acetonitrile (3 ml) and stirred for 40 minutes, the Reaction mixture was distributed between ethyl acetate and saturated aqueous sodium bicarbonate. The organic layer was washed with saturated aqueous sodium bicarbonate, water and saturated saline in this order, then dried over anhydrous sodium sulfate. The solvent is evaporated under reduced pressure, obtaining a residue, which is purified column chromatography on silica gel (eluent: hexane:ethyl acetate = 1:2). The fractions containing the target compound, concentrate, and get the remainder, which is suspended in a mixture of diethyl ether (1.5 ml) - hexane (1.5 ml). Solid prophetic the steam curing agent dried in a stream of air, which is specified in the header connection (125,7 mg, 75,3%) as a solid pale yellow color.

Range1H-NMR (DMSO-d6) δ (ppm): 2,95 (6H, c), 3,83 (2H, c), 7,19 (2H, m), 7,30 is 7.50 (5H, m), 7,88 (1H, m), 8,40 (1H, m), 9,60 (1H, c), to 11.79 (1H, Sirs), 12,41 (1H, Sirs).

Example 8

4-(Pyrrolidin-1-yl)piperidine-1-carboxylic acid {6-[2-fluoro-4-(3-phenylacetylamino)phenoxy]pyrimidine-4-yl}amide

2-Phenylacetylene (0,053 ml) dissolved in acetonitrile (4 ml) under nitrogen atmosphere, then adding potassium thiocyanate (77,7 mg) at 60°C and stirred at the same temperature for 2 hours. The reaction mixture is cooled to room temperature and distributed between ethyl acetate and saturated aqueous sodium bicarbonate. The organic layer was washed with saturated aqueous sodium bicarbonate, water and saturated saline in this order, then dried over anhydrous sodium sulfate. The solvent is evaporated, obtaining a residue, to which is added a solution of 4-(pyrrolidin-1-yl)piperidine-1-carboxylic acid [6-(4-amino-2-pertenece)pyrimidine-4-yl]amide (49,0 mg) in acetonitrile (5 ml) under nitrogen atmosphere, followed by stirring at room temperature for 1 hour. The reaction mixture is distributed between ethyl acetate and water. The organic layer was washed with saturated saline and Susitna anhydrous sodium sulfate. The solvent is evaporated under reduced pressure, obtaining a residue, which is purified column chromatography on silica gel (FUJI Silysia NH, eluent: ethyl acetate:methanol = 19:1). The crude product is again purified column chromatography on silica gel (FUJI Silysia NH, eluent: ethyl acetate:methanol = 19:1). The fractions containing the target compound, concentrate, and get the remainder, which is suspended in a mixture of diethyl ether (0.5 ml) - hexane (1.0 ml). The solid is filtered off, dried in the air flow and get listed in the title compound (8.1 mg, 11.5 per cent) in the form of a solid white color.

Range1H-NMR (CDCl3) δ (ppm): 1,48 is 1.70 (2H, m), is 1.81 (4H, m)of 1.97 (2H, m), of 2.25 (1H, m), 2,59 (4H, m), 3.04 from (2H, m), 3,70-of 3.80 (2H, m), a 4.03 (2H, m), 7,18 is 7.50 (8H, m), 7,63 (1H, c), 7,86 (1H, DD, J=2,4, and 11.6 Hz), 8,33 (1H, c), 8,49 (1H, Sirs), 12,43 (1H, Sirs).

Example 9

Pyrrolidin-1-carboxylic acid [4-(4-{3-[2-(4-forfinal)acetyl]touraid}phenoxy)pyridine-2-yl]amide

2-(4-Forfinal)acetylchloride (72,5 mg) dissolved in acetonitrile (2 ml) in nitrogen atmosphere, then adding potassium thiocyanate (81,6 mg) at 60°C and stirred at the same temperature for 2 hours. The reaction mixture is cooled to room temperature, add a solution of 4-(4-aminophenoxy)-2-[(pyrrolidin-1-yl)carbylamine]pyridine (50 mg) in acetonitrile (3 ml) and stirred for 1 hour. The reaction mixture was partitioned between those who acetate and saturated aqueous sodium bicarbonate. The organic layer was washed with saturated aqueous sodium bicarbonate, water and saturated saline in this order, then dried over anhydrous sodium sulfate. The solvent is evaporated under reduced pressure, obtaining a residue, which is purified column chromatography on silica gel (eluent: hexane:ethyl acetate = 1:1 to 1:3). The fractions containing the target compound, concentrate, and get the remainder, which is suspended in a mixture of diethyl ether (0.5 ml) - hexane (1.5 ml). The solid is filtered off, dried in the air flow and get listed in the title compound (15.8 mg, 19.1 percent) in the form of a solid pale yellow color.

Range1H-NMR (CDCl3) δ (ppm): a 1.96 (4H, m), of 3.45 (4H, m), 3,70 (2H, c), 6,55 (1H, DD, J=2,4, 5,6 Hz), 7,01 (1H, Sirs), 7,11 (4H, m), 7,29 (2H, m), 7,68 (2H, m), 7,73 (1H, d, J=2.4 Hz), with 8.05 (1H, d, J=5.6 Hz), to 8.57 (1H, m), of 12.26 (1H, Sirs).

Example 10

4-{2-Chloro-4-[3-(2-phenylacetyl)touraid]phenoxy}-2-[(pyrrolidin-1-yl)carbylamine]pyridine

2-Phenylacetylene (0,73 ml) dissolved in acetonitrile (5 ml) under nitrogen atmosphere, then adding potassium thiocyanate (107 mg) at 60°C and stirred at the same temperature for 2 hours. The reaction mixture is cooled to room temperature, add a solution of 4-(4-amino-2-chlorophenoxy)-2-[(pyrrolidin-1-yl)carbylamine]pyridine (122 mg) in acetonitrile (5 ml) and stirred at room is the temperature for 1.5 hours. The reaction mixture is distributed between ethyl acetate and saturated aqueous sodium bicarbonate. The organic layer was washed with saturated aqueous sodium bicarbonate and saturated saline in this order, then dried over anhydrous sodium sulfate. The solvent is evaporated under reduced pressure, obtaining a residue, which is purified column chromatography on silica gel (eluent: hexane:ethyl acetate = 1:4, then ethyl acetate). The fractions containing the target compound, concentrate, and get the remainder, to which add a small amount of diethyl ether to precipitate crystals. The slurry containing the crystals, diluted with a small amount of hexane. The crystals are filtered and dried in a stream of air, getting mentioned in the title compound (66,7 mg, 36%) as crystals pale yellow color.

Range1H-NMR (DMSO-d6) δ (ppm): 1,75-of 1.85 (4H, m), 3,20-3,40 (4H, m), 3,83 (2H, c), 6,56 (1H, DD, J=2,4, 5,6 Hz), 7,20-7,30 (6H, m), 7,45 (1H, d, J=2.4 Hz), 7,63 (1H, DD, J=2,4, 8,8 Hz), 8,10 (1H, d, J=2.4 Hz), 8,13 (1H, d, J=5.6 Hz), 8,68 (1H, c), 11,81 (1H, c), to 12.44 (1H, c).

Example 11

4-{2-Chloro-4-[3-(2-phenylacetyl)touraid]phenoxy}-2-[(morpholine-4-yl)carbylamine]pyridine

2-Phenylacetylene (0,93 ml) dissolved in acetonitrile (5 ml) under nitrogen atmosphere, then adding potassium thiocyanate (137 mg) at 60°C and stirred at the same temperature T. the value of 3 hours. The reaction mixture is cooled to room temperature, add a solution of 4-(4-amino-2-chlorophenoxy)-2-[(morpholine-4-yl)carbylamine]pyridine (164 mg) in acetonitrile (5 ml) and stirred at room temperature for 1 hour. The reaction mixture is distributed between ethyl acetate and saturated aqueous sodium bicarbonate. The organic layer was washed with saturated aqueous sodium bicarbonate and saturated saline in this order, then dried over anhydrous sodium sulfate. The solvent is evaporated under reduced pressure, obtaining a residue, which is purified column chromatography on silica gel (eluent: hexane:ethyl acetate = 1:4, then ethyl acetate). The fractions containing the target compound, concentrate, and get the remainder, which is suspended in a mixture of hexane/ethyl acetate (1/5). The obtained solid is filtered off, dried in the air flow and get listed in the title compound (115 mg, 47%) as a powder pale yellow color.

Range1H-NMR (DMSO-d6) δ (ppm): 3,30 is 3.40 (4H, m), 3,50-3,60 (4H, m), 3,83 (2H, c), 6,56 (1H, DD, J=2,4, 6,0 Hz), 7,20-7,40 (7H, m), of 7.64 (1H, DD, J=2,8, 8,8 Hz), of 8.09 (1H, d, J=2,8 Hz), 8,14 (1H, d, J=6.0 Hz), of 9.30 (1H, c), 11,81 (1H, c), 12,43 (1H, c).

Example 12

4-{2-Chloro-4-[3-(2-phenylacetyl)touraid]phenoxy}-6-[(pyrrolidin-1-yl)carbylamine]pyridine

2-Phenylacetylene (0,86 ml) dissolved in acetonitrile (5 m is) in nitrogen atmosphere, then add the potassium thiocyanate (127 mg) at 60°C and stirred at the same temperature for 3 hours. The reaction mixture is cooled to room temperature, add a solution of 4-(4-amino-2-chlorophenoxy)-6-[(pyrrolidin-1-yl)carbylamine]pyridine (145 mg) in acetonitrile (5 ml) and stirred at room temperature for 1.5 hours. The reaction mixture is distributed between ethyl acetate and saturated aqueous sodium bicarbonate. The organic layer was washed with saturated aqueous sodium bicarbonate and saturated saline in this order, then dried over anhydrous sodium sulfate. The solvent is evaporated under reduced pressure, obtaining a residue, which is purified column chromatography on silica gel (eluent: hexane:ethyl acetate = 1:2). The fractions containing the target compound, concentrate, and get the remainder, which is suspended in a mixture of diethyl ether/hexane (1/2). The obtained solid is filtered off, dried in the air flow and get listed in the title compound (122 mg, 55%) as white powder.

Range1H-NMR (DMSO-d6) δ (ppm): 1,80-1,90 (4H, m), 3,20-3,40 (4H, m), 3,83 (2H, c), 7,20-7,40 (6H, m), of 7.48 (1H, d, J=0.8 Hz), to 7.59 (1H, DD, J=2,4, 8,8 Hz), 8,00 (1H, d, J=2.4 Hz), 8,39 (1H, d, J=0.8 Hz), 9,41 (1H, c), RS 11.80 (1H, c), KZT 12.39 (1H, c).

Example 13

4-(2-Fluoro-4-{3-[2-(4-forfinal)acetyl]touraid}phenoxy)-2-[(pyrrole the Jn-1-yl)carbylamine]pyridine

Thionyl chloride (2.0 ml) are added to 2-(4-forfinal)acetic acid (694 mg) in a nitrogen atmosphere and stirred at 50°C for 1 hour. The reaction mixture was concentrated under reduced pressure, obtaining the remainder. The residue is dissolved in acetonitrile (100 ml) under nitrogen atmosphere, then adding potassium thiocyanate (875 mg) at 50°C and stirred at the same temperature for 2 hours. The reaction mixture is cooled to room temperature, add 4-(4-amino-2-pertenece)-2-[(pyrrolidin-1-yl)carbylamine]pyridine (949 mg) and stirred for 1 hour. The reaction mixture was concentrated under reduced pressure, obtaining a residue, which is then distributed between ethyl acetate and saturated aqueous sodium bicarbonate. The organic layer was washed with saturated saline and dried over anhydrous sodium sulfate. The solvent is evaporated under reduced pressure, obtaining a residue, which is purified column chromatography on silica gel (eluent: hexane:ethyl acetate = 1:2 to 1:3). The fractions containing the target compound, concentrate, and get the remainder, to which is added diethyl ether (20 ml)to precipitate crystals. The crystals are filtered and dried in a stream of air, getting mentioned in the title compound (834,5 mg, 54%) as white crystals.

Range1H-NMR (DMSO-d6) δ (ppm): 1,70-1,90(4H, m), 3,20-3,40 (4H, m), 3,83 (2H, c), 6,60 (1H, DD, J=2,4, 5,6 Hz), 7,18 (2H, m), 7,30-of 7.60 (5H, m), 7,98 (1H, m), 8,13 (1H, d, J=5.6 Hz), 8,73 (1H, c), RS 11.80 (1H, c), 12,47 (1H, c).

Example 14

4-{2-Fluoro-4-[3-(2-phenylacetyl)touraid]phenoxy}-2-[(pyrrolidin-1-yl)carbylamine]pyridine

2-Phenylacetylene (100 mg) dissolved in acetonitrile (2 ml) in nitrogen atmosphere, then adding potassium thiocyanate (126 mg) at 50°C and stirred at the same temperature for 1.5 hours. Add a solution of 4-(4-amino-2-pertenece)-2-[(pyrrolidin-1-yl)carbylamine]pyridine (41 mg) in acetonitrile (4 ml) and stirred at room temperature for 2.5 hours. The reaction mixture is cooled to room temperature and distributed between ethyl acetate and saturated aqueous sodium bicarbonate. The organic layer was washed with saturated saline and dried over anhydrous sodium sulfate. The solvent is evaporated under reduced pressure, obtaining a residue, which is purified column chromatography on silica gel (eluent: hexane:ethyl acetate = 1:4). The fractions containing the target compound, concentrate, and get the remainder, to which is added a small amount of diethyl ether to precipitate crystals. The slurry containing the crystals, diluted with a small amount of hexane. The crystals are filtered and dried in a stream of air, getting mentioned in the title compound (21,4 mg, 34%) as is kristallov pale yellow color.

Range1H-NMR (DMSO-d6) δ (ppm): 1,70-1,90 (4H, m), 3,20-3,40 (4H, m), 3,83 (2H, c), 6,60 (1H, m), 7,20-7,40 (6H, m), 7,50-of 7.60 (2H, m), to 7.99 (1H, m), 8,13 (1H, d, J=5.6 Hz), the rate of 8.75 (1H, c), 11,81 (1H, c), 12,50 (1H, c).

Example 15

4-{2-Fluoro-4-[3-(2-phenylacetyl)touraid]phenoxy}-2-[(4-hydroxypiperidine-1-yl)carbylamine]pyridine

2-Phenylacetylene (0,180 ml) dissolved in acetonitrile (20 ml) under nitrogen atmosphere, then adding potassium thiocyanate (197 mg) at 50°C and stirred at the same temperature for 2 hours. The reaction mixture was concentrated under reduced pressure, obtaining a residue, to which is added ethyl acetate (20 ml) and saturated aqueous sodium hydrogen carbonate solution (20 ml) followed by stirring for 30 minutes the Organic layer was separated, washed with saturated saline and dried over anhydrous sodium sulfate. The solvent is evaporated, obtaining 2-phenylacetonitrile, which is used to obtain a solution in a mixture of toluene (5 ml) - ethanol (5 ml). To the resulting solution was added 4-(4-amino-2-pertenece)-2-[(4-hydroxypiperidine-1-yl)carbylamine]pyridine (168 mg) and stirred over night. The reaction mixture was concentrated under reduced pressure, obtaining a residue, which is purified column chromatography on silica gel (eluent: ethyl acetate:methanol = 95:5). The fractions containing the target compound, concentrate, and get the remainder, which suspe dirout in diethyl ether (20 ml). The obtained solid is filtered off, dried in the air flow and get listed in the title compound (106 mg, 42%) as white powder.

Range1H-NMR (DMSO-d6) δ (ppm): 1,20-1,40 (2H, m), 1,60-1,80 (2H, m)3,00-3,20 (2H, m)to 3.64 (1H, m), 3,70-of 3.85 (2H, m), 3,83 (2H, c), and 4.68 (1H, d, J=4.4 Hz), to 6.58 (1H, DD, J=2,4, 6,0 Hz), 7,20-7,40 (7H, m)to 7.50 (1H, m), of 8.00 (1H, m), 8,13 (1H, d, J=6.0 Hz), which 9.22 (1H, c), 11,81 (1H, c), 12,49 (1H, c).

Example 16

2-[(Dimethylamino)carbylamine]-4-{2-fluoro-4-[3-(2-cyclohexylacetate)ureido]phenoxy}pyridine

2-Cyclohexylacetate (80 mg) was dissolved in acetonitrile (5 ml) under nitrogen atmosphere, then adding potassium thiocyanate (97 mg) at 50°C and stirred at the same temperature for 1 hour. The reaction mixture is cooled to room temperature, add 4-(4-amino-2-pertenece)-2-[(dimethylamino)carbylamine]pyridine (58 mg) and stirred for 30 minutes, the Reaction mixture was distributed between ethyl acetate and saturated aqueous sodium bicarbonate. The organic layer was washed with saturated aqueous sodium bicarbonate and saturated saline in this order, then dried over anhydrous sodium sulfate. The solvent is evaporated under reduced pressure, obtaining a residue, which is purified column chromatography on silica gel (eluent: hexane:ethyl acetate = 1:3). The fractions containing the target compound, the oxygen is their and get the remainder, to which is added diethyl ether (10 ml)to precipitate crystals. The slurry containing the crystals, diluted with hexane (20 ml). The crystals are filtered and dried in air stream, receiving specified in the header of the connection (of 45.6 mg, 48%) as white crystals.

Range1H-NMR (DMSO-d6) δ (ppm): to 0.80 and 1.80 (11H, m), a 2.36 (2H, d, J=6.8 Hz), 2,89 (6H, c), is 6.61 (1H, DD, J=2,4, 5,6 Hz), of 7.36-the 7.43 (2H, m), 7,53 (1H, DD, J=1,2, 8,8 Hz), 8,03 (1H, DD, J=2,4, 12.0 Hz), 8,13 (1H, d, J=5.6 Hz), to 8.94 (1H, c), 11,54 (1H, c), 12,68 (1H, c).

Example 17

2-[(Dimethylamino)carbylamine]-4-{2-fluoro-4-[3-(2-norbornanamine)ureido]phenoxy}pyridine

2-Norbornanamine acid (66 mg) is dissolved in thionyl chloride (0.5 ml) under nitrogen atmosphere and stirred at 50°C for 1 hour. The reaction mixture was concentrated under reduced pressure, obtaining the crude 2-norbornanamine. The crude 2-norbornanamine dissolved in acetonitrile (5 ml) under nitrogen atmosphere, then adding potassium thiocyanate (84 mg) at 50°C and stirred at the same temperature for 1 hour. The reaction mixture is cooled to room temperature, add 4-(4-amino-2-pertenece)-2-[(dimethylamino)carbylamine]pyridine (50 mg) and stirred for 30 minutes, the Reaction mixture was distributed between ethyl acetate and saturated aqueous sodium bicarbonate. The organic layer was washed with saturated aqueous solution of the m sodium bicarbonate and saturated saline in this order, then dried over anhydrous sodium sulfate. The solvent is evaporated and get the remainder, which is purified column chromatography on silica gel (eluent: hexane:ethyl acetate = 1:4). The fractions containing the target compound, concentrate, and get the remainder, to which is added diethyl ether (5 ml)to precipitate crystals. Containing crystals, the suspension was diluted with hexane (10 ml). The crystals are filtered and dried in air stream, receiving specified in the header of the connection (and 39.7 mg, 48%) as white crystals.

Range1H-NMR (DMSO-d6) δ (ppm): 0,60-2,30 (13H, m), 2,90 (6H, c), is 6.61 (1H, DD, J=2,4, 5,6 Hz), of 7.36-the 7.43 (2H, m), 7,52 (1H, d, J=8,8 Hz), 8,03 (1H, DD, J=2,4, 12.0 Hz), 8,13 (1H, d, J=5.6 Hz), to 8.94 (1H, c), 11,54 (1H, c), 12,65 (1H, c).

ESI-MS (m/z): 486 [M+1]+.

Example 18

Morpholine-4-carboxylic acid {4-[3-fluoro-4-(3-phenylacetylamino)phenoxy]pyridine-2-yl}amide

To a solution of 1-[4-(2-aminopyridine-4-yloxy)-2-forfinal]-3-(2-phenylacetyl)thiourea (270 mg) in tetrahydrofuran (12 ml), add triethylamine (0,142 ml), then with stirring and cooling in a bath with ice add phenylcarbamate (0,160 ml) and stirred under nitrogen atmosphere for 30 minutes part of the solution (4.0 ml), concentrated under reduced pressure, then added N,N-dimethylformamide (1.5 ml) and morpholine (0,989 ml, 1,14 mmol) and stirred at room temperature for 5 hours. The reaction to shift the ü distributed between ethyl acetate (40 ml) and water (40 ml). The organic layer was washed with saturated saline and dried over anhydrous sodium sulfate. The solvent is evaporated and get the remainder, which is purified column chromatography on silica gel (eluent: hexane:ethyl acetate = 1:1, ethyl acetate, then ethyl acetate:methanol = 10:1). The fractions containing the target compound, concentrate, and get a solid substance that is suspended in diethyl ether. The solid is filtered off, washed with diethyl ether and dried in a stream of air, getting mentioned in the title compound (42 mg) in the form of a powder pale brown color.

Range1H-NMR (DMSO-d6) δ (ppm): to 3.41 (4H, m), of 3.56 (4H, m), 3,83 (2H, c), 6,63 (1H, DD, J=2,2, 5.6 Hz), 7,05 (1H, d, J=8,8 Hz), 7,25-to 7.35 (6H, m), 7,46 (1H, m), 8,02 (1H, DD, J=8,8, 8,8 Hz), 8,17 (1H, d, J=5.6 Hz), was 9.33 (1H, c), 11,88 (1H, c), 12,24 (1H, c).

ESI-MS (m/z): 510 [M+1]+.

Example 19

Piperidine-1-carboxylic acid (4-{3-fluoro-4-[3-(2-phenylacetyl)touraid]phenoxy}pyridine-2-yl)amide

To a solution of 1-[4-(2-aminopyridine-4-yloxy)-2-forfinal]-3-(2-phenylacetyl)thiourea (270 mg) in tetrahydrofuran (12 ml), add triethylamine (0,142 ml), then with stirring and cooling in a bath with ice add phenylcarbamate (0,160 ml) and stirred under nitrogen atmosphere for 30 minutes the Third part of the solution concentrated under reduced pressure, then added N,N-dimethylformamide (1.5 ml) and piperidine (0,112 ml) and paramesh is live at room temperature for 5 hours. The reaction mixture is distributed between ethyl acetate (40 ml) and water (40 ml). The organic layer was washed with saturated saline and dried over anhydrous sodium sulfate. The solvent is evaporated and get the remainder, which is purified column chromatography on silica gel (eluent: hexane:ethyl acetate = 1:1, then ethyl acetate). The fractions containing the target compound, concentrate, and get a solid substance that is suspended in diethyl ether. The solid is filtered off, washed with diethyl ether and dried in a stream of air, getting mentioned in the title compound (50 mg) in powder form of a pale brown color.

Range1H-NMR (DMSO-d6) δ (ppm): 1,45 (4H, m), and 1.54 (2H, m), 3,39 (4H, m), 3,83 (2H, c), 6,60 (1H, DD, J=2,4, 5,6 Hz), 7,03 (1H, m), 7,24 and 7.36 (6H, m), 7,46 (1H, d, J=2.4 Hz), 8,01 (1H, m), 8,15 (1H, d, J=5.6 Hz), 9,19 (1H, c), 11.87 per (1H, c), 12,23 (1H, c).

Example 20

Pyrrolidin-1-carboxylic acid {4-[3-fluoro-4-(3-phenylacetylamino)phenoxy]pyridine-2-yl}amide

To a solution of 2-phenylacetylide (0,054 ml, 0.43 mmol) in acetonitrile (4.3 ml) is added potassium thiocyanate (83 mg) at room temperature and stirred under nitrogen atmosphere at 60°C for 1.5 hours. The reaction mixture is cooled in a bath with ice, then add a solution of pyrrolidin-1-carboxylic acid [4-(4-amino-3-pertenece)pyridine-2-yl]amide (90 mg) in acetonitrile (4.0 ml), the reaction mixture is heated decanates temperature and stirred for 3 hours. The reaction mixture is distributed between ethyl acetate and water. The organic layer was washed with saturated saline and dried over anhydrous sodium sulfate. The solvent is evaporated and get the remainder, which is purified column chromatography on silica gel (eluent: hexane:ethyl acetate = 1:1 to 1:2, then ethyl acetate). The fractions containing the target compound, concentrate, and get a solid substance that is suspended in diethyl ether. The solid is filtered off, washed with diethyl ether and dried in a stream of air, getting mentioned in the title compound (18 mg, 13%) as a colorless powder.

Range1H-NMR (DMSO-d6) δ (ppm): is 1.81 (4H, m)to 3.36 (4H, m), 3,83 (2H, c), 6,62 (1H, d, J=5.6 Hz),? 7.04 baby mortality (1H, m), 7,25 was 7.36 (6H, m), EUR 7.57 (1H, c), 8,02 (1H, m), 8,15 (1H, d, J=5.6 Hz), the rate of 8.75 (1H, c), 11,88 (1H, c), 12,24 (1H, c).

Example 21

Morpholine-4-carboxylic acid {4-[2-fluoro-4-(3-phenylacetylamino)phenoxy]pyridine-2-yl}amide

To a solution of morpholine-4-carboxylic acid [4-(4-amino-2-pertenece)pyridine-2-yl]amide (50 mg) in N,N-dimethylformamide (1.0 ml) is added phenylacetonitrile (42 mg) and stirred at room temperature for 22 hours. The reaction mixture is distributed between ethyl acetate and water. The organic layer was washed with saturated saline and dried over anhydrous sodium sulfate. The solvent is evaporated and get the rest of imaut column chromatography on silica gel (eluent: hexane:ethyl acetate = 1:1, the ethyl acetate, then ethyl acetate:methanol = 10:1). The fractions containing the target compound, concentrate, and get a solid substance that is suspended in diethyl ether. The solid is filtered off, washed with diethyl ether and dried in a stream of air, getting mentioned in the title compound (22 mg, 0,043 mmol, 29%) as a colourless solid.

Range1H-NMR (DMSO-d6) δ (ppm): 3.40 in (4H, m), 3,55 (4H, m), 3,83 (2H, c), is 6.61 (1H, d, J=5.8 Hz), 7,30 (1H, m), of 7.36 (6H, m), 7,51 (1H, d, J=9.6 Hz), to 7.99 (1H, m)to 8.14 (1H, d, J=5.8 Hz), to 9.32 (1H, c), 11,81 (1H, c), 12,49 (1H, c).

ESI-MS (m/z): 510 [M+H]+.

Example 22

1-(3-Diethylaminopropyl)-3-[4-(2-fluoro-4-{3-[2-(4-forfinal)acetyl]touraid}phenoxy)pyridine-2-yl]-1-metalmachine

To a solution of 1-[4-(2-aminopyridine-4-yloxy)-3-forfinal]-3-[(4-forfinal)acetyl]thiourea (100 mg) in tetrahydrofuran (10 ml), add triethylamine (0,101 ml), then with stirring and cooling in a bath with ice add phenylcarbamate (0,0454 ml) and stirred under nitrogen atmosphere for 10 minutes, the Reaction mixture was concentrated under reduced pressure, obtaining a residue, to which is added N,N-dimethylformamide (2.0 ml) and N,N-diethyl-N'-methyl-1,3-propandiamine (151 mg), followed by stirring at room temperature for 2.5 hours. The reaction mixture was diluted with ethyl acetate (150 ml), washed with saturated aqueous sodium hydrogen carbonate and su is at over anhydrous sodium sulfate. The solvent is evaporated and get the remainder, which is purified column chromatography on silica gel (FUJI Silysia NH, hexane:ethyl acetate = 1:2, then ethyl acetate). The fractions containing the target compound, concentrate, and get a solid, which is purified by LC-MS. The fractions containing the target compound, concentrate, and get a solid substance, to which is added a saturated aqueous solution of sodium bicarbonate for alkalizing. The mixture is extracted with ethyl acetate, the organic layer is dried over anhydrous sodium sulfate. The solvent is evaporated, getting mentioned in the title compound (2.7 mg, 1.9 per cent) in the form of oil pale yellow color.

Range1H-NMR (CDCl3) δ (ppm): 1,09 (6H, m), 1.60-to 1,90 (2H, m)to 2.06 (2H, m)of 2.75 (4H, m), is 2.88 (3H, c)to 3.34 (2H, m), the 3.65 (2H, c), 6,44 (1H, DD, J=2,4, 6,0 Hz), 7,00-to 7.09 (3H, m), 7,20-7,26 (3H, m), 7,47 (1H, m), 7,80 (1H, DD, J=2,4, and 11.6 Hz), to 7.99 (1H, d, J=6.0 Hz), 8,96 (1H, Sirs), 12,36 (1H, c).

ESI-MS (m/z) (neg.): 583 [M-H]-.

Example 23

Morpholine-4-carboxylic acid {4-[2-methyl-4-(3-phenylacetylamino)phenoxy]pyridine-2-yl}amide

To a solution of 2-phenylacetylide (0,0523 ml) in acetonitrile (5.0 ml) is added potassium thiocyanate (35.6 mg) and stirred under nitrogen atmosphere at 50°C for 1 hour. The reaction mixture is cooled to room temperature, then add morpholine-4-carboxylic acid [4-(4-amino-2-methylphenoxy)pyridine-2-yl]amide (80 mg) and N,N-dimethyl rmaed (1 ml) followed by stirring under nitrogen atmosphere at room temperature for 21 hours. The reaction mixture is distributed between ethyl acetate (100 ml) and water (40 ml). The organic layer was washed with saturated saline and dried over anhydrous sodium sulfate. The solvent is evaporated and get the remainder, which is purified column chromatography on silica gel (eluent:ethyl acetate). The fractions containing the target compound, concentrate, and get a solid substance that is suspended in a mixture of diethyl ether (4 ml) - ethanol (0.8 ml). The solid is filtered off, washed with diethyl ether and dried in a stream of air, getting mentioned in the title compound (38 mg, 31%) as a colorless powder.

Range1H-NMR (DMSO-d6) δ (ppm): 2,10 (3H, c), 3,39 (4H, m), 3,55 (4H, m), 3,82 (2H, c), 6,51 (1H, DD, J=2,4, 5,6 Hz), 7,10 (1H, d, J=8,4 Hz), 7,28 and 7.36 (6H, m), 7,60-to 7.64 (2H, m), 8,11 (1H, d, J=5.6 Hz), 9,24 (1H, c), 11,72 (1H, c), 12,43 (1H, c).

ESI-MS (m/z)(neg.): 504 [M-H]-.

Example 24

Morpholine-4-carboxylic acid (4-{2-methyl-4-[3-(4-forfinal)acetylthiourea]phenoxy}pyridine-2-yl)amide

To a solution of 2-(4-forfinal)acetylchloride (to 63.2 mg) in acetonitrile (30 ml) was added potassium thiocyanate (35.6 mg), followed by stirring in nitrogen atmosphere at 50°C for 1 hour. The reaction mixture is cooled to room temperature, then add morpholine-4-carboxylic acid [4-(4-amino-2-methylphenoxy)pyridine-2-yl]amide (80 mg) and stirred under nitrogen atmosphere for 2 hours. Rea is operating, the mixture is distributed between ethyl acetate (100 ml) and water (60 ml). The organic layer was washed with saturated saline and dried over anhydrous sodium sulfate. The solvent is evaporated and get the remainder, which is purified column chromatography on silica gel (eluent: hexane:ethyl acetate = 2:5, then ethyl acetate). The fractions containing the target compound, concentrate, receiving the oil, which is then added to diethyl ether and again concentrated under reduced pressure, obtaining a solid substance. The obtained solid is then suspended in a mixture of diethyl ether (4 ml) - ethanol (0.4 ml), filtered off, washed with diethyl ether and dried in a stream of air, getting mentioned in the title compound (14 mg, 11%) as colorless powder.

Range1H-NMR (DMSO-d6) δ (ppm): 2,10 (3H, c), 3,39 (4H, m), 3,55 (4H, m), 3,82 (2H, c), 6,51 (1H, DD, J=2,4, 6,0 Hz), 7,10 (1H, d, J=8,4 Hz), 7,18 (2H, m), 7,31 (1H, d, J=2.4 Hz), 7,38 (2H, DD, J=5,8, 8,8 Hz), 7,60-7,66 (2H, m), 8,11 (1H, d, J=6.0 Hz), 9,24 (1H, c), 11,72 (1H, c), 12,40 (1H, c).

ESI-MS (m/z) (neg.): 522 [M-H]-.

Example 25

Pyrrolidin-1-carboxylic acid {4-[2-methyl-4-(3-phenylacetylamino)phenoxy]pyridine-2-yl}amide

To a solution of 2-phenylacetylide (0,0549 ml) in acetonitrile (5.0 ml) is added potassium thiocyanate (37,3 mg, 0.384 mmol) and stirred under nitrogen atmosphere at 50°C for 1 hour. The reaction mixture is cooled to room temperature, then add pyrrolidin-1-carboxylic acid [4-(4-amino-2-IU is elfenix)pyridine-2-yl]amide (80 mg) and stirred under nitrogen atmosphere for 21 hours. The reaction mixture is distributed between ethyl acetate (100 ml) and water (40 ml). The organic layer was washed with saturated saline and dried over anhydrous sodium sulfate. The solvent is evaporated and get the remainder, which is purified column chromatography on silica gel (eluent: ethyl acetate). The fractions containing the target compound, concentrate, and get a solid substance that is suspended in diethyl ether (4 ml). The solid is filtered off and dried in a stream of air, getting mentioned in the title compound (51 mg, 41%) as a colorless powder.

Range1H-NMR (DMSO-d6) δ (ppm): 1,80 (4H, m), 2,11 (3H, c)to 3.33 (4H, m), 3,83 (2H, c), of 6.49 (1H, d, J=5.6 Hz), 7,00 (1H, d, J=9.0 Hz), 7,30 (1H, m), 7,35 (4H, m), 7,42 (1H, c), to 7.61 (1H, c), to 7.64 (1H, d, J=9.0 Hz), of 8.09 (1H, d, J=5.6 Hz), 8,66 (1H, c), 11,72 (1H, c), to 12.44 (1H, c).

ESI-MS (m/z)(neg.): 488 [M-H]-.

Example 26

Pyrrolidin-1-carboxylic acid (4-{2-methyl-4-[3-(4-forfinal)acetylthiourea]phenoxy}pyridine-2-yl)amide

To a solution of 2-(4-forfinal)acetylchloride (to 66.3 mg) in acetonitrile (30 ml) was added potassium thiocyanate (37,3 mg) and stirred under nitrogen atmosphere at 50°C for 1 hour. The reaction mixture is cooled to room temperature, then add pyrrolidin-1-carboxylic acid [4-(4-amino-2-methylphenoxy)pyridine-2-yl]amide (80 mg) and stirred under nitrogen atmosphere for 2 hours. The reaction mixture was partitioned between ethyl what cetecom (100 ml) and water (60 ml). The organic layer was washed with saturated saline and dried over anhydrous sodium sulfate. The solvent is evaporated and get the remainder, which is purified column chromatography on silica gel (eluent: hexane:ethyl acetate = 1:3, then ethyl acetate). The fractions containing the target compound, concentrate, and get the remainder, to which is added diethyl ether and again concentrated under reduced pressure, obtaining a solid substance. The obtained solid is then suspended in a mixture of diethyl ether (4 ml) - ethanol (0.4 ml), filtered off, washed with diethyl ether and dried in a stream of air, getting mentioned in the title compound (15 mg, 11,5%) as a colorless powder.

Range1H-NMR (DMSO-d6) δ (ppm): 1,80 (4H, m), 2,10 (3H, c)to 3.33 (4H, m), 3,82 (2H, c), of 6.50 (1H, DD, J=2,4, 5,6 Hz), 7,10 (1H, d, J=8,8 Hz), 7,18 (2H, m), 7,38 (2H, DD, J=6,0, 8,4 Hz), 7,42 (1H, d, J=2.4 Hz), to 7.59-7,65 (2H, m), of 8.09 (1H, d, J=5.6 Hz), 8,65 (1H, c), 11,71 (1H, c), 12,41 (1H, c).

ESI-MS (m/z) (neg.): 506 [M-H]-.

Example 27

1-(3-Dimethylaminopropyl)-3-{6-[2-fluoro-4-(3-phenylacetylamino)phenoxy]pyrimidine-4-yl}-1-metalmachine

2-Phenylacetylene (0,032 ml) dissolved in acetonitrile (3 ml) under nitrogen atmosphere, then adding potassium thiocyanate (46.6 mg) at 60°C and stirred at the same temperature for 2 hours. The reaction mixture is cooled to room temperature, then add ethyl acetate and saturated the initial aqueous sodium hydrogen carbonate solution, followed by stirring for 30 minutes The organic layer is separated, washed with saturated aqueous sodium bicarbonate, water and saturated saline in this order, then dried over anhydrous sodium sulfate. The solvent is evaporated, obtaining a residue which is then dissolved in a mixture of toluene (1 ml) - ethanol (1 ml), then add a solution of 3-[6-(4-amino-2-pertenece)pyrimidine-4-yl]-1-(3-diethylaminopropyl)-1-metalmachine in a mixture of toluene (1.5 ml) - ethanol (1.5 ml) in nitrogen atmosphere, followed by stirring at room temperature for 2 hours. The reaction mixture is distributed between ethyl acetate and water. The organic layer was washed with saturated saline and dried over anhydrous sodium sulfate. The solvent is evaporated and get the remainder, which is purified column chromatography on silica gel (FUJI Silysia NH, eluent: heptane:ethyl acetate = 1:1). The fractions containing the crude product, concentrate, and get the remainder, which is purified column chromatography on silica gel (FUJI Silysia NH, eluent: heptane:ethyl acetate = 1:1). The fractions containing the target compound, concentrate, and get the remainder, which is dried in vacuum, obtaining mentioned in the title compound (6.0 mg, 12.5 percent) in the form of a solid white color.

Range1H-NMR (CDCl3) δ (ppm)with 1.07 (6H, t, J=6.8 Hz), of 1.80 (2H, m)of 2.50 (2H, t, J=5.6 Hz), 2,68 (4H, m), of 2.92 (3H, c), 3,40 (2H, t, J=5.6 Hz), 3,74 (H, c), 7,15-7,52 (9H, m), to 7.84 (1H, DD, J=2,4, and 11.6 Hz), 8,30 (1H, c), 8,43 (1H, Sirs), 12,40 (1H, Sirs).

ESI-MS (m/z): 568 [M+H]+.

Example 28

3-{4-[2-Fluoro-4-(3-phenylacetylamino)phenoxy]pyridine-2-yl}-1-methyl-1-(1-methylpiperidin-4-yl)urea

2-Phenylacetylene (0,032 ml) dissolved in acetonitrile (3 ml) under nitrogen atmosphere, then adding potassium thiocyanate (46.6 mg) at 60°C, followed by stirring at the same temperature for 2 hours. The reaction mixture is cooled to room temperature, then add ethyl acetate and saturated aqueous sodium hydrogen carbonate solution, followed by stirring for 30 minutes the Organic layer is separated, washed with saturated aqueous sodium bicarbonate, water and saturated saline in this order, then dried over anhydrous sodium sulfate. The solvent is evaporated, obtaining a residue, to which is added a mixture of toluene (1 ml) - ethanol (1 ml) to obtain a solution. 3-[4-(4-Amino-2-pertenece)pyridine-2-yl]-1-methyl-1-(1-methylpiperidin-4-yl)urea (40,0 mg) is dissolved in ethanol (1 ml) in nitrogen atmosphere, then add D-10-camphorsulfonic acid (24,9 mg) and stirred for 5 minutes To the reaction mixture previously obtained a solution of 2-phenylacetonitrile in a mixture of toluene-ethanol (2 ml) and stirred at room temperature for 30 minutes, the Reaction mixture distribute settled between ethyl acetate and saturated aqueous sodium bicarbonate. The organic layer was washed with saturated aqueous sodium bicarbonate, water and saturated saline in this order, then dried over anhydrous sodium sulfate. The solvent is evaporated and get the remainder, which is purified column chromatography on silica gel (FUJI Silysia NH, eluent: ethyl acetate). The fractions containing the target compound, concentrate, and get the remainder, which is suspended in a mixture of diethyl ether (0.5 ml) - hexane (1.0 ml). The solid is filtered off, dried in the air flow and get listed in the title compound (10.3 mg, 17.5%) each in the form of a solid white color.

Range1H-NMR (CDCl3) δ (ppm): 1,50-1,70 (2H, m)to 1.79 (2H, m), 2,10 (2H, m)to 2.29 (3H, m), 2,84-of 3.00 (5H, m in), 3.75 (2H, m), 4,18 (1H, m), is 6.54 (1H, m), 7,19 (2H, m), 7,20 is 7.50 (6H, m), of 7.69 (1H, d, J=2.4 Hz), 7,89 (1H, DD, J=2,4, and 11.6 Hz), of 8.06 (1H, d, J=5.6 Hz), 8,49 (1H, Sirs), to 12.44 (1H, Sirs).

ESI-MS (m/z): 551 [M+H]+.

Example 29

3-{4-[2-Fluoro-4-(3-phenylacetylamino)phenoxy]pyridine-2-yl}-1-methyl-1-[3-(4-methylpiperazin-1-yl)propyl]urea

2-Phenylacetylene (0,032 ml) dissolved in acetonitrile (3 ml) under nitrogen atmosphere, then adding potassium thiocyanate (46.6 mg) at 60°C and stirred at the same temperature for 2 hours. The reaction mixture is cooled to room temperature, then add ethyl acetate and a saturated aqueous solution of sodium bicarbonate and stirred t is within 30 minutes The organic layer is separated, washed with saturated aqueous sodium bicarbonate, water and saturated saline in this order, then dried over anhydrous sodium sulfate. The solvent is evaporated, obtaining a residue, to which is added acetonitrile (2 ml) to obtain a solution. 3-[4-(4-Amino-2-pertenece)pyridine-2-yl]-1-methyl-1-[3-(4-methylpiperazin-1-yl)propyl]urea (50.0 mg) was dissolved in ethanol (1 ml) in nitrogen atmosphere, then add D-10-camphorsulfonic acid (24,9 mg) followed by stirring for 5 minutes To the reaction mixture previously obtained a solution of 2-phenylacetonitrile in acetonitrile (2 ml) and stirred under nitrogen atmosphere at room temperature throughout the night. The reaction mixture is distributed between ethyl acetate and saturated aqueous sodium bicarbonate. The organic layer was washed with saturated aqueous sodium bicarbonate, water and saturated saline in this order, then dried over anhydrous sodium sulfate. The solvent is evaporated and get the remainder, which is purified column chromatography on silica gel (FUJI Silysia NH, eluent: heptane:ethyl acetate=1:5 to 1:8). The fractions containing the target compound, concentrate, and get the remainder, which is suspended in a mixture of diethyl ether (1.5 ml) - hexane (1.5 ml). Solid vases is sucked in, dried in a stream of air, which is specified in the header connection (35,0 mg, 49.1 per cent) in the form of a solid white color.

Range1H-NMR (CDCl3) δ (ppm): to 1.61 (4H, m), of 1.78 (2H, m)to 2.35 (3H, c), is 2.40 (2H, t, J=6.0 Hz), 2,69 (4H, m), 2,89 (3H, c), 3,39 (2H, t, J=6.0 Hz), 3,74 (2H, c), of 6.50 (1H, DD, J=2,4, 5,6 Hz), 7,16 (1H, m), 7,26 (1H, c), 7,31 (3H, m), 7,34-of 7.48 (3H, m), 7,60 (1H, d, J=2.4 Hz), 7,88 (1H, DD, J=2,4, 12.0 Hz), with 8.05 (1H, d, J=5.6 Hz), 8,55 (1H, Sirs), 12,43 (1H, Sirs).

ESI-MS (m/z): 594 [M+H]+.

Example 30

1-(1-Methylpiperidin-4-yl)-3-{4-[2-fluoro-4-(3-phenylacetylamino)phenoxy]pyridine-2-yl}urea

1-[4-(2-Aminopyridine-4-yloxy)-3-forfinal]-3-phenylacetylamino (50 mg) dissolved in tetrahydrofuran (1.3 ml) under stirring, then add N-methylmorpholine (0,040 ml) and phenylcarbamate (0,040 ml) in that order in a nitrogen atmosphere, cooling in a bath with ice, after which the temperature was increased to room temperature and stirred for 10 minutes, the Reaction mixture was distributed between ethyl acetate (15 ml) and saturated aqueous sodium hydrogen carbonate (10 ml). The organic layer was washed with saturated aqueous sodium hydrogen carbonate (10 ml), water (10 ml) and saturated saline (10 ml) in that order, then dried over anhydrous sodium sulfate. The solvent is evaporated, obtaining {4-[2-fluoro-4-(3-phenylacetylamino)phenoxy]pyridine-2-yl}carbamino acid phenyl ester in the crude form. Untreated the i.i.d. product is dissolved in N,N-dimethylformamide (1.3 ml), then added at room temperature N-methylmorpholin (0.100 ml) and 4-amino-1-methylpiperidin (101 mg), followed by stirring for 1 hour. The reaction mixture is distributed between ethyl acetate (15 ml) and saturated aqueous sodium hydrogen carbonate (10 ml). The organic layer was washed with saturated aqueous sodium hydrogen carbonate (10 ml), water (10 ml) and saturated saline (10 ml) in that order, then dried over anhydrous sodium sulfate. The solvent is evaporated and get the remainder, which is purified column chromatography on silica gel (FUJI Silysia NH, eluent: ethyl acetate, then ethyl acetate:ethanol = 9:1). The fractions containing the target compound, concentrate, and get the remainder, which is suspended in a mixture of diethyl ether (1 ml) - hexane (2 ml). The solid is filtered off, dried in a stream of air, which is specified in the header connection (67,6 mg, 56.2 per cent) in the form of a solid white color.

Range1H-NMR (CDCl3) δ (ppm): 1,50-1,72 (2H, m), a 2.01 (2H, m), 2,19 (2H, m)to 2.29 (3H, c), by 2.73 (2H, m), 3.72 points-of 3.85 (3H, m), 6,13 (1H, m), is 6.54 (1H, DD, J=2,4, 6,0 Hz), 7,16 (1H, m), 7,27-7,46 (7H, m), 7,89 (1H, DD, J=the 2.4, 12.0 Hz), with 8.05 (1H, d, J=6.0 Hz), 9,44 (2H, m), 12,58 (1H, Sirs).

ESI-MS (m/z): 537 [M+H]+.

Example 31

1-Methyl-1-(1-methylpiperidin-4-yl)-3-{4-[4-(3-phenylacetylamino)phenoxy]pyridine-2-yl}urea

3-[4-(4-Aminophenoxy)pyridine-2-yl]-1-methyl-1-(1-methylpiperidin--yl)urea (60 mg) dissolved in ethanol (1 ml) under stirring, then add D-10-camphorsulfonic acid (39,3 mg) in a nitrogen atmosphere and stirred for 5 minutes Then add phenylacetonitrile (toluene solution, 1,82M, 0,074 ml) and stirred for further 1.5 hours. The reaction mixture is distributed between ethyl acetate (30 ml) and saturated aqueous sodium hydrogen carbonate (20 ml). The organic layer was washed with saturated aqueous sodium bicarbonate, water and saturated saline in this order, then dried over anhydrous sodium sulfate. The solvent is evaporated and get the remainder, which is purified column chromatography on silica gel (Fuji Silysia NH, eluent: hexane:ethyl acetate = 1:5, then ethyl acetate). The fractions containing the crude product, concentrate, and get the remainder, which is then purified by LC-MS. The fractions containing the target compound, concentrate, and get the remainder, to which is added a saturated aqueous solution of sodium bicarbonate, followed by extraction with ethyl acetate. The organic layer is separated and dried over anhydrous sodium sulfate. The solvent is evaporated and get the remainder, which is purified column chromatography on silica gel (Fuji Silysia NH, eluent: ethyl acetate, then ethyl acetate:ethanol = 9:1). The fractions containing the target compound, concentrate, and get the remainder, which is suspended in a mixture of diethyl the IDF (0.3 ml) - hexane (0.1 ml). The solid is filtered off, dried in the air flow and get listed in the title compound (2.0 mg, 2.2 percent) in the form of a solid white color.

Range1H-NMR (CDCl3) δ (ppm):1,45-to 1.63 (2H, m), of 1.78 (2H, m), is 2.09 (2H, m)to 2.29 (3H, c), 2,88-2,96 (5H, m in), 3.75 (2H, c), 4,18 (1H, m), is 6.54 (1H, DD, J=2,0, 5.6 Hz), 7,11 (2H, m), 7,18 (1H, Sirs), 7,32 (2H, m), 7,37-7,47 (3H, m), 7,66-7,72 (3H, m), of 8.06 (1H, d, J=5.6 Hz), 8,44 (1H, Sirs), 12,30 (1H, Sirs).

ESI-MS (m/z): 533 [M+H]+.

Example 32

4-(Pyrrolidin-1-yl)piperidine-1-carboxylic acid {4-[3-fluoro-4-(3-phenylacetylamino)phenoxy]pyridine-2-yl}amide

4-(Pyrrolidin-1-yl)piperidine-1-carboxylic acid [4-(4-amino-3-pertenece)pyridine-2-yl]amide was dissolved in ethanol (3.0 ml), then add (S)-(+)-10-camphorsulfonic acid (75,5 mg) and stirred at room temperature for 15 minutes Add the solution phenylacetonitrile (to 45.5 mg) in toluene (3.0 ml) and stirred at room temperature for 2.5 hours. The reaction mixture is distributed between ethyl acetate (50 ml) and saturated aqueous sodium hydrogen carbonate (30 ml). The organic layer was washed with saturated saline (30 ml×3) and dried over anhydrous sodium sulfate. The solvent is evaporated and get the remainder, which is purified column chromatography on silica gel (FUJI Silysia NH, eluent: heptane:ethyl acetate = 1:2, ethyl acetate, then ethyl acetate). Fractions provided the target compound, concentrate and get a solid substance, to which is added diethyl ether (3 ml) and hexane (3 ml) in order to obtain the suspension. The solid is filtered off, washed with diethyl ether (1 ml) and dried in air stream, receiving specified in the header connection (17,8 mg, 18%) as a colorless powder.

Range1H-NMR (DMSO-d6) δ (ppm): 1.28 (in 2H, m)of 1.66 (4H, m)to 1.79 (2H, m)to 2.13 (1H, m), 2,47 (4H, m), 2,87 (2H, m), 3,83 (2H, c), of 3.97 (2H, m), 6,60 (1H, DD, J=2,4, 5,6 Hz), 7,03 (1H, d, J=9,2 Hz), 7.24 to 7,38 (6H, m), was 7.45 (1H, d, J=2.4 Hz), 8,01 (1H, m), 8,15 (1H, d, J=5.6 Hz), the 9.25 (1H, c), 11,88 (1H, Sirs), 12,23 (1H, Sirs).

ESI-MS (m/z): 577 [M+H]+.

Example 33

1-(3-Diethylaminopropyl)-3-{4-[3-fluoro-4-(3-phenylacetylamino)phenoxy]pyridine-2-yl}-1-metalmachine

To a solution of 1-[4-(2-aminopyridine-4-yloxy)-2-forfinal]-3-phenylacetylglutamine (69,4 mg) in tetrahydrofuran (2.0 ml) is added triethylamine (0,0488 ml) and phenylcarbamate (0,0329 ml) in that order in a nitrogen atmosphere, followed by stirring at room temperature for 10 minutes the Solution is concentrated under reduced pressure, then added N,N-dimethylformamide (1.0 ml) and N,N-diethyl-N'-methylpropan-1,3-diamine (101 mg) and stirred at room temperature for 10.5 hours. The reaction mixture was partitioned between water (30 ml) and ethyl acetate (50 ml). The organic layer was washed with saturated saline solution (30 ml) and dried over betwedn the m sodium sulfate. The solvent is evaporated and get the remainder, which is purified column chromatography on silica gel (Fuji Silysia NH, heptane:ethyl acetate = 1:2, ethyl acetate, then ethyl acetate:methanol = 20:1). The fractions containing the target compound, concentrate, and get a solid substance, to which is added diethyl ether (1 ml) and hexane (1 ml) to give a suspension. The solid is filtered off, dried in the air flow and get listed in the title compound (15.8 mg, 15,9%) as a colorless powder.

Range1H-NMR (CDCl3) δ (ppm): of 1.06 (6H, t, J=7.2 Hz), or 1.77 (2H, m), 2.49 USD (2H, m), 2,65 (4H, q, J=7.2 Hz), 2,90 (3H, c), 3,39 (2H, m in), 3.75 (2H, c), 6,48 (1H, DD, J=2,4, 5,6 Hz), 6.89 in (2H, m), 7,31 was 7.45 (5H, m), to 7.61 (1H, d, J=2.4 Hz), 8,07 (1H, d, J=5.6 Hz), of 8.27 (1H, m), charged 8.52 (1H, Sirs), 12,29 (1H, c).

ESI-MS (m/z: 567 [M+H]+.

Example 34

3-{4-[3-Fluoro-4-(3-phenylacetylamino)phenoxy]pyridine-2-yl}-1-methyl-1-(1-methylpiperidin-4-yl)urea

A solution of 3-[4-(4-amino-3-pertenece)pyridine-2-yl]-1-methyl-1-(1-methylpiperidin-4-yl)urea in tetrahydrofuran (20 ml)obtained in example getting 124, concentrated almost to dryness. To the residue is added ethanol (3.0 ml), then (S)-(+)-10-camphorsulfonic acid (48,1 mg) added and stirred at room temperature for 15 minutes Add the solution phenylacetonitrile (29 mg) in toluene (3.0 ml) and stirred at room temperature for 2.5 hours. The reaction mixture distribution is jut between ethyl acetate (50 ml) and saturated aqueous sodium hydrogen carbonate (30 ml). The organic layer was washed with saturated saline (30 ml×3) and dried over anhydrous sodium sulfate. The solvent is evaporated and get the remainder, which is purified column chromatography on silica gel (FUJI Silysia NH, eluent: heptane:ethyl acetate = 1:2, ethyl acetate, then ethyl acetate:methanol = 20:1). The fractions containing the target compound, concentrate, and get the remainder, which is suspended in diethyl ether (1 ml) and hexane (5 ml). The suspension is left to stand for 10 min, the supernatant removed and the remaining solvent evaporated under reduced pressure. The obtained solid is dried in vacuum, obtaining mentioned in the title compound (20.5 mg, 34,2%) as a colorless powder.

Range1H-NMR (CDCl3) δ (ppm): 1,64-to 1.82 (4H, m), 2.05 is-2,11 (2H, m)to 2.29 (3H, c), 2,88-of 2.93 (5H, m), 3,76 (2H, c), 4,17 (1H, m), 6,56 (1H, DD, J=2,0, 5.6 Hz), 6.90 to-6,93 (2H, m), 7,17 (1H, Sirs), 7,31-7,33 (2H, m), 7,37-7,46 (3H, m), of 7.75 (1H, d, J=2.0 Hz), 8,31 (1H, m), of 8.47 (1H, Sirs), of 12.33 (1H, c).

ESI-MS (m/z): 551 [M+H]+, 573 [M+Na]+.

Example 35

3-[4-(3-Fluoro-4-{3-[2-(4-forfinal)acetyl]touraid}phenoxy)pyridine-2-yl]-1,1-dimethyloxetane

To a solution of 1-[4-(2-aminopyridine-4-yloxy)-2-forfinal]-3-[2-(4-forfinal)acetyl]thiourea (26 mg) in tetrahydrofuran (2.0 ml) is added triethylamine (0,0175 ml) and phenylcarbamate (0,0118 ml) in that order in a nitrogen atmosphere, followed by stirring at room temperature in accordance with the ie 10 minutes The solution is concentrated under reduced pressure, obtaining a residue which is then dissolved in N,N-dimethylformamide (1.0 ml). Add triethylamine (0,0873 ml) and dimethylamine hydrochloride (25.6 mg) and stirred at room temperature for 24 hours. To the reaction mixture are added water (30 ml) and ethyl acetate (50 ml) and stirred at room temperature for 4 hours. The organic layer was separated, washed with saturated saline solution (30 ml) and dried over anhydrous sodium sulfate. The solvent is evaporated and get the remainder, which is purified column chromatography on silica gel (Fuji Silysia NH, heptane:ethyl acetate = 1:2, ethyl acetate, then ethyl acetate:methanol = 20:1). The fractions containing the target compound, concentrate, and get the remainder, which is cleaned again column chromatography on silica gel (eluent: heptane:ethyl acetate = 1:2, ethyl acetate, then ethyl acetate:methanol = 20:1). The fractions containing the target compound, concentrate, getting solid pale yellow color (83,7 mg), which was suspended in ethyl acetate (1 ml) and hexane (3 ml). The solid is filtered off, dried in the air flow and get listed in the title compound (4.8 mg, 15,8%) as a colorless powder.

Range1H-NMR (CDCl3) δ (ppm): 3,03 (6H, c), and 3.72 (2H, c), 6,56 (1H, DD, J=2,4, 5,6 Hz), 6,92 (2H, m), 7,12 (2H, m), 7,21 (1H, m), 7,21-7,28 (2H, m), 7,73 (1H, d, J=2.4 Hz), 8,08 (1H, m), 833 (1H, m), 8,54 (1H, Sirs), of 11.29 (1H, c).

ESI-MS (m/z) (neg.): 484 [M-H]-.

Example 36

4-{4-[3-(2-Phenylacetyl)touraid]phenoxy}-2-{[4-(pyrrolidin-1-yl)piperidine-1-yl]carbylamine}pyridine

2-Phenylacetylene (0,040 ml) dissolved in acetonitrile (2.0 ml) in nitrogen atmosphere, then adding potassium thiocyanate (60 mg) at 50°C and stirred at the same temperature for 3 hours. The acetonitrile is evaporated under reduced pressure, obtaining a residue, to which is added toluene (2.0 ml) and saturated aqueous sodium hydrogen carbonate solution (2.0 ml) followed by stirring for 15 minutes the Toluene layer (0.7 ml) are added to a solution of 4-(4-aminophenoxy)-2-{[4-(pyrrolidin-1-yl)piperidine-1-yl]carbylamine}pyridine (27 mg) and (S)-(+)-10-camphorsulfonic acid (32 mg) in ethanol (1.0 ml) at room temperature, followed by stirring for 30 minutes the Reaction mixture is distributed between ethyl acetate and saturated aqueous sodium bicarbonate. The organic layer was washed with saturated aqueous sodium bicarbonate and saturated saline in this order, then dried over anhydrous sodium sulfate. The solvent is evaporated and get the remainder, which is purified column chromatography on silica gel (Fuji Silysia NH, eluent: ethyl acetate). The fractions containing the target compound are concentrated under reduced pressure and the rest are square, which is then dried in vacuum, obtaining specified in the header connection (17,2 mg, 44%) as white powder.

Range1H-NMR (CDCl3) δ (ppm): 1,45-to 1.60 (2H, m), 1,70-1,90 (4H, m), 1,90-2,00 (2H, m), of 2.23 (1H, m), 2,50-to 2.65 (4H, m), of 2.97 (2H, m), 3,74 (2H, c), a 4.03 (2H, m), 6,53 (1H, DD, J=2,4, 5,6 Hz), 7,11 (2H, d, J=8,8 Hz), 7,30 is 7.50 (6H, m), of 7.64 (1H, d, J=2.4 Hz), to 7.68 (2H, d, J=8,8 Hz), 8,03 (1H, d, J=5.6 Hz), 8,50-to 8.70 (1H, W), 12,31 (1H, c).

ESI-MS (m/z): 559 [M+1]+

Example 37

4-{2-Fluoro-4-[3-(2-phenylacetyl)touraid]phenoxy}-2-[(4-oxopiperidin-1-yl)carbylamine]pyridine

2-Amino-4-{2-fluoro-4-[3-(2-phenylacetyl)touraid]phenoxy}pyridine (100 mg) dissolved in tetrahydrofuran (2.5 ml) under nitrogen atmosphere, is added dropwise N-methylmorpholine (0,080 ml) and phenylcarbamate (0,080 ml), cooling in a bath with ice, then increase the temperature to room temperature and stirred for 20 minutes the Reaction mixture is distributed between ethyl acetate and saturated aqueous sodium bicarbonate. The organic layer was washed with saturated aqueous sodium bicarbonate and saturated saline in this order, then dried over anhydrous sodium sulfate. The solvent is evaporated, obtaining a residue which is dissolved in N,N-dimethylformamide (2.5 ml), and then add N-methylmorpholine (0.2 ml) and the monohydrate hydrochloride 4-oxopiperidine (272 mg) at room temperature, followed by stirring for 23 hours of the century The reaction mixture is distributed between ethyl acetate and saturated aqueous sodium bicarbonate. The organic layer was washed with saturated aqueous sodium bicarbonate and saturated saline in this order, then dried over anhydrous sodium sulfate. The solvent is evaporated and get the remainder, which is purified column chromatography on silica gel (eluent: ethyl acetate). The fractions containing the target compound are concentrated under reduced pressure and get the remainder, which is dried in vacuum, obtaining specified in the header connection (83,1 mg, 63%) as white powder.

Range1H-NMR (CDCl3) δ (ppm): 2,40-2,60 (4H, m in), 3.75 (2H, c), 3,76-a 3.83 (4H, m), to 6.57 (1H, m), 7,20 was 7.45 (8H, m), of 7.64 (1H, c), to $ 7.91 (1H, DD, J=2,4, 12.0 Hz), 8,07 (1H, d, J=5.6 Hz), 8,48 (1H, c), 12,46 (1H, c).

Example 38

2-{[4-(dimethylamino)piperidine-1-yl]carbylamine}-4-{2-fluoro-4-[3-(2-phenylacetyl)touraid]phenoxy}pyridine

To a solution of 4-{2-fluoro-4-[3-(2-phenylacetyl)touraid]phenoxy}-2-[(4-oxopiperidin-1-yl)carbylamine]pyridine (38 mg) in dichloromethane (2.0 ml) is added dimethylamine HCl (15 mg) and triacetoxyborohydride sodium (40 mg) at room temperature, followed by stirring overnight. The reaction mixture is distributed between ethyl acetate and saturated aqueous sodium bicarbonate. The organic layer was washed with saturated aqueous Rast is the PR of sodium bicarbonate and saturated saline in this order, then dried over anhydrous sodium sulfate. The solvent is evaporated and get the remainder, which is purified column chromatography on silica gel (Fuji Silysia NH, eluent: ethyl acetate:methanol = 95:5). The fractions containing the target compound are concentrated under reduced pressure and get the remainder, which is dried in vacuum, obtaining specified in the header of the connection (of 22.8 mg, 57%) as white powder.

Range1H-NMR (CDCl3) δ (ppm): 1,40-of 1.55 (2H, m), 1,80-of 1.95 (2H, m), 2,28 (6H, c), of 2.34 (1H, m), 2,85-2,95 (2H, m), 3,74 (2H, c), 4,05-to 4.15 (2H, m), 6,53 (1H, DD, J=2,4, 5,6 Hz), 7,10 was 7.45 (8H, m), 7,63 (1H, d, J=2.4 Hz), 7,89 (1H, DD, J=2,4, 12.0 Hz), with 8.05 (1H, d, J=5.6 Hz), 8,51 (1H, W), to 12.44 (1H, c).

ESI-MS (m/z): 551 [M+1]+

Example 39

2-{[4-(Azetidin-1-yl)piperidine-1-yl]carbylamine}-4-{2-fluoro-4-[3-(2-phenylacetyl)touraid]phenoxy}pyridine

To a solution of 4-{2-fluoro-4-[3-(2-phenylacetyl)touraid]phenoxy}-2-[(4-oxopiperidin-1-yl)carbylamine]pyridine (38 mg) in dichloromethane (2.0 ml) is added the hydrochloride of azetidine (17 mg) and triacetoxyborohydride sodium (40 mg) at room temperature, followed by stirring overnight. The reaction mixture is distributed between ethyl acetate and saturated aqueous sodium bicarbonate. The organic layer was washed with saturated aqueous sodium bicarbonate and saturated saline in this order, then dried over anhydrous sulfate on the model. The solvent is evaporated and get the remainder, which is purified column chromatography on silica gel (Fuji Silysia NH, eluent: ethyl acetate:methanol = 95:5). The fractions containing the target compound are concentrated under reduced pressure and get the remainder, which is dried in vacuum, obtaining mentioned in the title compound (31.9 per mg, 78%) as white powder.

Range1H-NMR (CDCl3) δ (ppm): 1,50-1,80 (4H, m), 2.00 in of 2.10 (2H, m), 2,19 (1H, m), 3.00 and-of 3.07 (2H, m), of 3.10-3.20 (4H, m), 3,74 (2H, c), 3,80-of 3.95 (2H, m), 6,53 (1H, DD, J=2,4, 5,6 Hz), 7,10 was 7.45 (8H, m), a 7.62 (1H, d, J=2,4 Hz), 7,88 (1H, DD, J=2,4, 12.0 Hz), of 8.04 (1H, d, J=5.6 Hz), 8,51 (1H, W), to 12.44 (1H, c).

ESI-MS (m/z): 563 [M+1]+

Example 40

4-{2-Fluoro-4-[3-(2-phenylacetyl)touraid]phenoxy}-2-{[4-(pyrrolidin-1-yl)piperidine-1-yl]carbylamine}pyridine

2-Amino-4-{2-fluoro-4-[3-(2-phenylacetyl)touraid]phenoxy}pyridine (66,6 mg) dissolved in tetrahydrofuran (2.0 ml) under nitrogen atmosphere, is added dropwise N-methylmorpholine (0,0462 ml) and phenylcarbamate (0,0527 ml) in that order, cooling in a bath with ice, then increase the temperature to room temperature and stirred for 15 minutes the Solvent is evaporated, obtaining a residue which is dissolved in N,N-dimethylformamide (2.0 ml), then add 4-(pyrrolidin-1-yl)piperidine (136 mg) at room temperature and stirred for 2 hours. The reaction mixture is distributed between ethyl acetate and saturated aqueous Rast is the PR of sodium bicarbonate. The organic layer was washed with saturated aqueous sodium bicarbonate and saturated saline in this order, then dried over anhydrous sodium sulfate. The solvent is evaporated and get the remainder, which is purified column chromatography on silica gel (Fuji Silysia NH, eluent: ethyl acetate:methanol = 95:5). The fractions containing the target compound are concentrated under reduced pressure and get the remainder, which is dried in vacuum, obtaining specified in the header connection (46,3 mg, 48%) as white powder.

Range1H-NMR (CDCl3) δ (ppm): 1,50-1,60 (2H, m), 1,75-of 1.85 (4H, m), 1,90 is 1.96 (2H, m), of 2.20 (1H, m), 2,50-2,60 (4H, m), of 2.97 (2H, m), 3,74 (2H, c), 3,95-of 4.05 (2H, m), 6,53 (1H, DD, J=2,4, 5,6 Hz), 7,15-7,47 (8H, m), 7,63 (1H, d, J=2.4 Hz), 7,89 (1H, DD, J=2,4, 12.0 Hz), with 8.05 (1H, d, J=5.6 Hz), of 8.47 (1H, Sirs), 12,43 (1H, c).

ESI-MS (m/z): 577 [M+1]+.

Example 41

3-{6-[2-Fluoro-4-(3-phenylacetylamino)phenoxy]pyrimidine-4-yl}-1-methyl-1-(1-methylpiperidin-4-yl)urea

3-[6-(4-Amino-2-pertenece)pyrimidine-4-yl}-1-methyl-1-(1-methylpiperidin-4-yl)urea (50 mg) dissolved in ethanol (1 ml), then add D-10-camphorsulfonic acid (62.3 mg) and stirred for 5 minutes Add phenylacetonitrile (toluene solution, 0,355M, of 0.565 ml) and stirred for further 1 hour. The reaction mixture is distributed between ethyl acetate (30 ml) and saturated aqueous sodium hydrogen carbonate (20 ml). Organizes the th layer is washed with saturated aqueous sodium hydrogen carbonate (20 ml), water (20 ml) and saturated saline (20 ml) in this order, then dried over anhydrous sodium sulfate. The solvent is evaporated and get the remainder, which is purified column chromatography on silica gel (Fuji Silysia NH, eluent: ethyl acetate). The fractions containing the target compound, concentrate, and get the remainder, to which is added a mixture of diethyl ether (0.5 ml) - hexane (2.0 ml)to suspended solid. The solid is filtered off, dried in a stream of air, which is specified in the header connection (12,4 mg, 16.8 percent) in the form of a powder pale yellow color.

Range1H-NMR (CDCl3) δ (ppm): 1.30 and 1,72 (2H, m), is 1.81 (2H, m), 2,11 (2H, m), 2,31 (3H, c), 2,60-3,10 (5H, m), 3,74 (2H, c), 4,19 (1H, m), 7,00-of 7.60 (8H, m), 7,68 (1H, c), 7,86 (1H, DD, J=2,11 Hz), a 8.34 (1H, c), to 8.45 (1H, Sirs), 12,43 (1H, Sirs).

ESI-MS (m/z): 552 [M+H]+.

Example 42

1,1-Dimethyl-3-{4-[4-(3-phenylacetylamino)phenoxy]pyridine-2-yl}urea

2-Phenylacetamide (149 mg) was dissolved in 1,2-dichloroethane (10 ml) under nitrogen atmosphere, then add oxalicacid (0,175 ml) and stirred at 110°C during the night. The reaction mixture was concentrated under reduced pressure, obtaining a residue which is dissolved in N,N-dimethylformamide (3.4 ml) in nitrogen atmosphere. Then add 3-[4-(4-aminophenoxy)pyridine-2-yl]-1,1-dimethyloxetane (100 mg) and stirred for 30 minutes, the Reaction mixture was partitioned between atilas what tatom and water. The organic layer is washed with water and saturated saline in this order, then dried over anhydrous sodium sulfate. The solvent is evaporated and get the remainder, which is purified column chromatography on silica gel (eluent: hexane:ethyl acetate = 1:3). The fractions containing the crude product, concentrated under reduced pressure and get the remainder, which is then distributed between ethyl acetate and 1 N. hydrochloric acid. The aqueous layer was alkalinized 1 N. aqueous sodium hydroxide solution and then extracted with ethyl acetate. The organic layer is washed with water and saturated saline in this order, then dried over anhydrous sodium sulfate. The solvent is evaporated, obtaining the crude product, which is then distributed between ethyl acetate and 1 N. hydrochloric acid. The aqueous layer was alkalinized 1 N. aqueous sodium hydroxide solution and then extracted with ethyl acetate. The organic layer is washed with water and saturated saline in this order, then dried over anhydrous sodium sulfate. The solvent is evaporated, obtaining the crude product, which is again distributed between ethyl acetate and 1 N. hydrochloric acid. The aqueous layer was alkalinized 1 N. aqueous sodium hydroxide solution and then extracted with ethyl acetate. About the organic layer washed with water and saturated saline in this order, then dried over anhydrous sodium sulfate. The solvent is evaporated, obtaining the crude product, which was distributed between ethyl acetate and 1 N. hydrochloric acid. The aqueous layer was alkalinized 1 N. aqueous sodium hydroxide solution and then extracted with ethyl acetate. The organic layer is washed with water and saturated saline in this order, then dried over anhydrous sodium sulfate. The solvent is evaporated, obtaining a residue, to which is added a small amount of ethyl acetate and a small amount of hexane to precipitate crystals. The crystals are filtered and dried in a stream of air, getting mentioned in the title compound (8.1 mg, 5.1 per cent) in the form of crystals of pale yellow color.

Range1H-NMR (DMSO-d6) δ (ppm): 2,88 (6H, c), of 3.73 (2H, Sirs), 6,56 (1H, m), 7,11 (2H, d, J=8,4 Hz), 7,25 was 7.45 (6H, m), 7,60 (2H, d, J=8,4 Hz), of 8.09 (1H, d, J=5.6 Hz), 8,86 (1H, Sirs), 10,52 (1H, Sirs), 10,98 (1H, Sirs).

Example 43

4-{2-Fluoro-4-[3-(2-phenylacetyl)ureido]phenoxy}-2-[(pyrrolidin-1-yl)carbylamine]pyridine

2-Phenylacetamide (128 mg) was dissolved in 1,2-dichloroethane (10 ml) under nitrogen atmosphere, then add oxalicacid (0,103 ml) and stirred at 120°C during the night. The reaction mixture was concentrated under reduced pressure and get a residue, which was dissolved in N,N-dimethylformamide (3.2 ml) in nitrogen atmosphere. Then add 4-(4-amino-pertenece)-2-[(pyrrolidin-1-yl)carbylamine]pyridine (100 mg) and stirred for 30 minutes The reaction mixture is distributed between ethyl acetate and saturated aqueous sodium bicarbonate. The organic layer is washed with water and saturated saline in this order, then dried over anhydrous sodium sulfate. The solvent is evaporated, receiving the remnant that purify column chromatography on silica gel (FUJI Silysia NH, eluent: hexane:ethyl acetate = 1:3). The fractions containing the target compound, concentrate, and get the remainder, to which is added a mixture of ethyl acetate (2 ml) - hexane (10 ml)to precipitate crystals. The crystals are filtered and dried in a stream of air, getting mentioned in the title compound (113 mg, 75%) as white crystals.

Range1H-NMR (DMSO-d6) δ (ppm): 1,70-1,90 (4H, m), 3,20-3,40 (4H, m), 3,74 (2H, c), 6,60 (1H, m), 7,20 is 7.50 (8H, m), to 7.77 (1H, m), 8,10 (1H, d, J=5.6 Hz), to 8.70 (1H, c), 10,61 (1H, c), 11,04 (1H, c).

Example 44

2-[(Dimethylamino)carbylamine]-4-{2-fluoro-4-[3-(2-phenylacetyl)ureido]phenoxy}pyridine

2-Phenylacetamide (126 mg) was dissolved in 1,2-dichloroethane (10 ml) under nitrogen atmosphere, then add oxalicacid (0,101 ml) and stirred at 110°C during the night. The reaction mixture was concentrated under reduced pressure and get a residue, which was dissolved in N,N-dimethylformamide (3 ml) under nitrogen atmosphere. Then add 4-(4-amino-2-pertenece)-2-[(dimethylamino)carbylamine]pyridine (90 mg) and paramesh who live within 20 minutes The reaction mixture is distributed between ethyl acetate and water. The organic layer was washed with saturated aqueous sodium bicarbonate and saturated saline in this order, then dried over anhydrous sodium sulfate. The solvent is evaporated and get the remainder, which is purified column chromatography on silica gel (FUJI Silysia NH, eluent: hexane:ethyl acetate = 1:3). The fractions containing the target compound, concentrate, and get the remainder, to which is added ethyl acetate (1.5 ml)to precipitate crystals. The crystals are filtered and dried in a stream of air, getting mentioned in the title compound (36,3 mg, 26%) as white crystals.

Range1H-NMR (CDCl3) δ (ppm): a 3.01 (6H, c in), 3.75 (2H, c), 6,53 (1H, m), 7,00-7,80 (10H, m), of 8.04 (1H, m), to 8.20 (1H, c), 10,61 (1H, c).

Example 45

4-{2-Fluoro-4-[3-(2-phenylacetyl)ureido]phenoxy}-2-{[4-(pyrrolidin-1-yl)piperidine-1-yl]carbylamine}pyridine

2-Phenylacetamide (203 mg) was dissolved in 1,2-dichloroethane (20 ml) under nitrogen atmosphere, then add oxalicacid (0,174 ml) and stirred at 120°C during the night. The reaction mixture was concentrated under reduced pressure and get a residue, which was dissolved in N,N-dimethylformamide (5 ml) under nitrogen atmosphere. Then add 4-(4-amino-2-pertenece)-2-{[4-(pyrrolidin-1-yl)piperidine-1-yl]carbylamine}pyridine (295 mg) and stirred for 1 hour is. The reaction mixture is distributed between ethyl acetate and saturated aqueous sodium bicarbonate. The organic layer is washed with water and saturated saline in this order, then dried over anhydrous sodium sulfate. The solvent is evaporated and get the remainder, which is purified column chromatography on silica gel (FUJI Silysia NH, eluent: ethyl acetate:methanol = 98:2). The fractions containing the target compound are concentrated under reduced pressure, obtaining a residue in the form of a brown powder, which is then dissolved in ethyl acetate (10 ml) and extracted with 1 N. hydrochloric acid (5 ml). The aqueous layer was neutralized by adding dropwise 1 N. aqueous sodium hydroxide solution, and stirred overnight. The precipitated solid is filtered off, washed with water and dried in a stream of air at 60°C, getting mentioned in the title compound (116 mg, 28%) as a powder pale pink color.

Range1H-NMR (CDCl3) δ (ppm): 1,40-1,60 (2H, m), 1,60-1,80 (4H, m), 1,90-2,00 (2H, m), of 2.20 (1H, m), 2,50-2,60 (4H, m), 2,90-of 3.00 (2H, m in), 3.75 (2H, c), 3,90-of 4.05 (2H, m), of 6.52 (1H, DD, J=2,4, 5,6 Hz), 7,10 was 7.45 (8H, m), to 7.59-to 7.64 (2H, m), 7,78 (1H, c), 8,03 (1H, d, J=5.6 Hz), 10,57 (1H, c).

Example 46

Pyrrolidin-1-carboxylic acid {6-[2-fluoro-4-(3-phenylacetylamino)phenoxy]pyrimidine-4-yl}amide

To a suspension of 2-phenylacetamide (905 mg, 6.7 mmol) in dichloroethane (90 ml) is added oxalyl the ID (1.75 ml, of 20.1 mmol) under nitrogen atmosphere, followed by stirring at 110°C for 12 hours. The reaction mixture is cooled to room temperature and concentrated under reduced pressure, obtaining a residue, to which is added hexane (13.4 ml), to obtain the solution fenilizotsianata in hexane. To a solution of pyrrolidin-1-carboxylic acid [6-(4-amino-2-pertenece)pyrimidine-4-yl]amide (40 mg) in N,N-dimethylformamide (1.0 ml) is added previously obtained solution fenilizotsianata in hexane (supernatant, 0,948 ml) in nitrogen atmosphere, followed by stirring at room temperature for 1 hour. The reaction mixture is distributed between ethyl acetate (50 ml) and saturated aqueous sodium hydrogen carbonate (20 ml). The organic layer is dried over anhydrous sodium sulfate. The solvent is evaporated, obtaining a residue which is suspended in ethyl acetate (1.0 ml). The solid is filtered off, washed with diethyl ether and dried in air stream, receiving specified in the header connection (47,1 mg, 78,1%) in the form of a powder pale yellow color.

Range1H-NMR (DMSO-d6) δ (ppm): to 1.83 (4H, m), 3,40 (4H, m), of 3.73 (2H, c), 7,25 was 7.36 (7H, m), 7,44 (1H, c), of 7.69 (1H, m), of 8.37 (1H, DD, J=1.2 Hz), 9,38 (1H, c), 10,56 (1H, c), br11.01 (1H, c).

ESI-MS (m/z): 479 [M+H]+, 501 [M+Na]+.

Example 47

Pyrrolidin-1-carboxylic acid {4-[3-chloro-4-(3-phenylacetylamino)phenoxy]pyridine-2-yl}and the ID

Pyrrolidin-1-carboxylic acid [4-(4-amino-3-chlorophenoxy)pyridine-2-yl]amide (20 mg) dissolved in N,N-dimethylformamide (1.0 ml), then add a solution fenilizotsianata in hexane is 0.019 ml, the sample receiving 1) and stirred at room temperature for 1 hour. To the reaction mixture are added ethyl acetate and water and spread the mixture. The organic layer was washed with saturated saline and dried over anhydrous sodium sulfate. The solvent is evaporated, receiving the remainder, which is then suspended in a mixture of ethyl acetate:methanol = 1:1. The solid is filtered off, washed with methanol and dried in a stream of air, getting mentioned in the title compound (10 mg, 34%) as a powder pale yellow color.

Range1H-NMR (DMSO-d6) δ (ppm): 1,78 (4H, m)to 3.36 (4H, m), 3,74 (2H, c), 6,56 (1H, DD, J=2,4, 5,6 Hz), 7,17 (1H, DD, J=2,4, 9,2 Hz), 7,26-to 7.35 (5H, m), 7,42 (1H, d, J=2.4 Hz), 7,47 (1H, d, J=2.4 Hz), 8,10 (1H, d, J=5,6 Hz), 8,30 (1H, d, J=9,2 Hz), 8,69 (1H, c), 11,04 (1H, c), 11,18 (1H, c).

Example 48

Morpholine-4-carboxylic acid {4-[2-fluoro-4-(3-phenylacetylamino)phenoxy]pyridine-2-yl}amide

To a solution of morpholine-4-carboxylic acid [4-(4-amino-2-pertenece)pyridine-2-yl]amide (54 mg) in N,N-dimethylformamide (1.0 ml) add a solution fenilizotsianata in hexane (0,972 ml, the sample receiving 1) and stirred at room temperature for 25 hours. The reaction mixture was partitioned between utilize the atom (50 ml) and water (30 ml). The organic layer was washed with saturated saline and dried over anhydrous sodium sulfate. The solvent is evaporated and get the remainder, which is purified column chromatography on silica gel (eluent: hexane:ethyl acetate = 1:1 to 1:2, ethyl acetate, ethyl acetate:methanol = 20:1 to 10:1). The fractions containing the target compound, concentrate, and get a solid substance that is suspended in ethyl acetate. The solid is filtered off, washed with ethyl acetate and dried in the air flow, getting mentioned in the title compound (9.5 mg, 12%) as a colorless powder.

Range1H-NMR (DMSO-d6) δ (ppm): 3.40 in (4H, m), 3,55 (4H, m), 3,74 (2H, c), is 6.61 (1H, DD, J=2,0, 5.6 Hz), 7,27-7,40 (8H, m), to 7.77 (1H, DD, J=2,4, 8,8 Hz), 8,13 (1H, d, J=5.6 Hz), 9.28 are (1H, c), 10,61 (1H, c)11,05 (1H, c).

ESI-MS (m/z): 516 [M+Na]+.

Example 49

1-(3-Diethylaminopropyl)-3-{4-[2-fluoro-4-(3-phenylacetylamino)phenoxy]pyridine-2-yl}-1-metalmachine

To a solution of 1-(3-diethylaminopropyl)-3-[4-(4-amino-2-pertenece)pyridine-2-yl]-1-metalmachine (100 mg) in tetrahydrofuran (2.0 ml) add a solution fenilizotsianata in hexane (3.4 ml, the sample receiving 1) and stirred under nitrogen atmosphere at room temperature for 30 minutes Then add a solution fenilizotsianata in hexane (1.0 ml, the sample receiving 1) and stirred at room temperature for 30 minutes, the Reaction mixture was distributed m is waiting with a mixture of ethyl acetate-tetrahydrofuran (1:1, 200 ml) and saturated aqueous sodium hydrogen carbonate (15 ml). The organic layer was washed with 1 N. aqueous sodium hydroxide solution and dried over anhydrous sodium sulfate. The solvent is evaporated and get the remainder, which is purified column chromatography on silica gel (FUJI Silysia NH, eluent: ethyl acetate). The fractions containing the crude product, concentrate, and get the remainder, which is then dissolved in ethyl acetate and washed with 1 N. aqueous sodium hydroxide solution. The organic layer is dried over anhydrous sodium sulfate. The solvent is evaporated, obtaining a residue, to which is added diethyl ether (3 ml) and hexane (3 ml)to precipitate a solid. The solid is filtered off, washed with diethyl ether and dried in a stream of air, getting mentioned in the title compound (8.3 mg/, 5,9%) as a colorless powder.

Range1H-NMR (DMSO-d6) δ (ppm): 0,97 (6H, t, J=7.2 Hz), 1,67 (2H, m), 2,35 (2H, m), 2,52 (4H, m), and 2.79 (3H, c), or 3.28 (2H, m), 3,74 (2H, c), is 6.54 (1H, DD, J=2,4, 5,6 Hz), 7,27-7,40 (8H, m), 7,76 (1H, DD, J=2,4, 8,8 Hz), 8,07 (1H, d, J=5.6 Hz), or 10.60 (1H, c), 11,04 (1H, c).

ESI-MS (m/z): 551 [M+H]+.

Example 50

4-Methylpiperazin-1-carboxylic acid {4-[2-fluoro-4-(3-phenylacetylamino)phenoxy]pyridine-2-yl}amide

To a solution of 4-methylpiperazin-1-carboxylic acid [4-(4-amino-2-pertenece)pyridine-2-yl]amide (80 mg) in tetrahydrofuran (2.3 ml) add a solution phenylacetic the isocyanate in hexane (1.4 ml, an example of retrieving 1) and stirred under nitrogen atmosphere at room temperature for 2 hours. The reaction mixture is distributed between ethyl acetate (100 ml) and saturated aqueous sodium hydrogen carbonate (50 ml). The organic layer is dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue is purified column chromatography on silica gel (FUJI Silysia NH, eluent: hexane:ethyl acetate = 1:1, ethyl acetate, then ethyl acetate:methanol = 10:1). The fractions containing the target compound, concentrate, and get the crude product, to which is added diethyl ether to precipitate a solid. The solid is filtered off, washed with diethyl ether and dried in air stream, receiving specified in the header connection (55,2 mg, 47%) as a colorless powder.

Range1H-NMR (DMSO-d6) δ (ppm): of 2.16 (3H, c in), 2.25 (4H, m), 3,40 (4H, m), 3,74 (2H, c), 6,59 (1H, DD, J=2,4, 5,6 Hz), 7,27-7,40 (8H, m), 7,76 (1H, DD, J=2,4, 8,8 Hz), 8,11 (1H, d, J=5.6 Hz), 9,23 (1H, c), or 10.60 (1H, c), 11,04 (1H, c).

ESI-MS (m/z): 507 [M+H]+

Example 51

3-[6-(2-Fluoro-4-{3-[2-(4-forfinal)acetyl]ureido}phenoxy)pyrimidine-4-yl]-1,1-dimethyloxetane

2-(4-Forfinal)ndimethylacetamide (125 mg) was dissolved in 1,2-dichloroethane (9 ml) under nitrogen atmosphere, then add oxalicacid (0.10 ml) and stirred at 110°C during the night. The reaction mixture was concentrated under reduced pressure, getting the rest, the which is dissolved in N,N-dimethylformamide (1 ml) under nitrogen atmosphere. Then add a solution of 3-[6-(4-amino-2-pertenece)pyrimidine-4-yl]-1,1-dimethyloxetane (90 mg) in N,N-dimetilformamide (2 ml) and stirred for 30 minutes, the Reaction mixture was distributed between ethyl acetate and water. The organic layer was washed with saturated aqueous sodium bicarbonate, water and saturated saline in this order, then dried over anhydrous sodium sulfate. The solvent is evaporated and get the remainder, which is purified column chromatography on silica gel (eluent: hexane:ethyl acetate = 1:3). The fractions containing the target compound, concentrate, and get the remainder, which is suspended in a mixture of diethyl ether (2 ml) - hexane (1 ml). The solid is filtered off, dried in a stream of air, which is specified in the header connection (72.4 mg, 49.8%) in the form of a solid pale yellow color.

Range1H-NMR (CDCl3) δ (ppm): a 3.06 (6H, m), and 3.72 (2H, c), 7,10 (2H, m), 7,16 (2H, m), 7,20-7,40 (3H, m), 7,50-of 7.70 (2H, m), a 8.34 (2H, Sirs), of 10.58 (1H, Sirs).

ESI-MS (m/z) (neg.): 469 [M-H]-.

Example 52

3-{4-[2-Fluoro-4-(3-phenylacetylamino)phenoxy]pyridine-2-yl]-1-methyl-1-(1-methylpiperidin-4-yl)urea

3-[4-(4-Amino-2-pertenece)pyridine-2-yl]-1-methyl-1-(1-methylpiperidin-4-yl)urea (50.0 mg) was dissolved in tetrahydrofuran (2 ml) in nitrogen atmosphere, then add a solution fenilizotsianata in toluene (0,80 ml, 0,5M solution that is whole, an example of retrieving 1) and stirred for 1 hour. The reaction mixture is distributed between ethyl acetate and saturated aqueous sodium bicarbonate. The organic layer was washed with saturated aqueous sodium bicarbonate, water and saturated saline in this order, then dried over anhydrous sodium sulfate. The solvent is evaporated and get the remainder, which is purified column chromatography on silica gel (FUJI Silysia NH, eluent: ethyl acetate:ethanol = 9:1). The fractions containing the target compound, concentrate, and get the remainder, which is suspended in a mixture of diethyl ether (1 ml) - hexane (0.5 ml). The solid is filtered off, dried in a stream of air, which is specified in the header connection (63,1 mg, 88.1 per cent) in the form of a solid pale yellow color.

Range1H-NMR (CDCl3) δ (ppm): 1,40-of 1.62 (2H, m), 1.70 to of 1.84 (2H, m), is 2.05 (2H, m), 2,28 (3H, c), 2,84-to 2.94 (5H, m), 3,76 (2H, c), of 4.16 (1H, m), of 6.52 (1H, m), 7,08-7,19 (3H, m), 7,30 (2H, m), 7,34-7,46 (3H, m), 7,58-7,74 (3H, m), of 8.04 (1H, d, J=6.0 Hz), 10,57 (1H, Sirs).

ESI-MS (m/z): 535 [M+H]+.

Example 53

4-(Pyrrolidin-1-yl)piperidine-1-carboxylic acid {4-[3-fluoro-4-(3-phenylacetylamino)phenoxy]pyridine-2-yl}amide

To a solution of benzyl 2-[fluoro-4-(2-{[4-(pyrrolidin-1-yl)piperidine-1-carbonyl]amino}pyridine-4-yloxy)phenyl]carbamate (165 mg) in tetrahydrofuran (5.0 ml) is added 10% palladium on coal (32,9 mg) and premesis the Ute in the atmosphere of hydrogen at room temperature for 25 hours. After replacing the hydrogen on the nitrogen added tetrahydrofuran (5.0 ml) and 10% palladium on coal (32,9 mg), followed by stirring in an atmosphere of hydrogen at room temperature for 2 hours. The catalyst removed from the reaction mixture by filtration and washed with a small amount of tetrahydrofuran (4 ml). To the filtrate add phenylacetonitrile (1,84 ml solution in hexane, the sample receiving 1) and stirred under nitrogen atmosphere at room temperature for 1 hour. Add another portion of fenilizotsianata (1,84 ml solution in hexane, the sample receiving 1) and stirred for 1 hour. To the reaction mixture are added ethyl acetate (50 ml) and saturated saline (30 ml) and distribute the mixture. The organic layer was washed with saturated saline (30 ml×3) and dried over anhydrous sodium sulfate. The solvent is evaporated and get the remainder, which is purified column chromatography on silica gel (FUJI Silysia NH, eluent: heptane:ethyl acetate = 1:2, ethyl acetate, then ethyl acetate:ethanol = 20:1). The fractions containing the target compound, concentrate, and get a pale red solid (94 mg), which was suspended in diethyl ether (3 ml). The solid is filtered off, washed with diethyl ether and dried in air stream, receiving specified in the header connection (75,4 mg, 43.5 per cent) in the form of a powder pale red color is the same.

Range1H-NMR (DMSO-d6) δ (ppm): 1.28 (in 2H, m)of 1.66 (4H, m), of 1.78 (2H, m), 2,12 (1H, m), 2,46 (4H, m), of 2.86 (2H, m in), 3.75 (2H, c), of 3.97 (2H, m), to 6.58 (1H, DD, J=2,0, 5.6 Hz), 7,02 (1H, d, J=9,2 Hz), 7,26-7,39 (7H, m), to 8.12 (1H, d, J=5.6 Hz), 8,17 (1H, m), of 9.21 (1H, c), of 10.76 (1H, c), 11,17 (1H, c).

ESI-MS (m/z): 561 [M+H]+.

Example 54

3-{4-[3-Fluoro-4-(3-phenylacetylamino)phenoxy]pyridine-2-yl}-1,1-dimethyloxetane

To a solution of benzyl {4-[2-(3,3-dimethylurea)pyridine-4-yloxy]-2-forfinal}carbamate (86,9 mg) in tetrahydrofuran (5.0 ml) is added 10% palladium on coal (to 21.8 mg) and stirred under hydrogen atmosphere at room temperature for 25 hours. The catalyst removed from the reaction mixture by filtration and washed with a small amount of tetrahydrofuran. To the obtained filtrate add phenylacetonitrile (1.23 ml, solution in hexane, the sample receiving 1) and stirred under nitrogen atmosphere at room temperature for 1 hour. To the reaction mixture are added ethyl acetate (50 ml) and water (30 ml) and distribute the mixture. The organic layer was washed with saturated saline (30 ml×3), and dried over anhydrous sodium sulfate. The solvent is evaporated and get the remainder, which is purified column chromatography on silica gel (eluent: ethyl acetate ethyl acetate:methanol = 20:1). The fractions containing the target compound, concentrate, and get a solid pale yellow color (83,7 mg), which suspended the mixture of ethyl acetate (1 ml) - diethyl ether (3 ml). The solid is filtered off and dried in air stream, receiving specified in the header connection (48,0 mg, 51,9%) as a colorless powder.

Range1H-NMR (DMSO-d6) δ (ppm): 2,90 (6H, c in), 3.75 (2H, c), 6,60 (1H, DD, J=2,4, 6,0 Hz), 7,03 (1H, d, J=8,8 Hz), 7,22-7,46 (7H, m)to 8.12 (1H, m), 8,18 (1H, m), of 8.92 (1H, c), of 10.76 (1H, c), 11,17 (1H, c).

ESI-MS (m/z): 474 [M+Na]+.

Example 55

N-(3-Fluoro-4-{2-[(Morpholine-4-carbonyl)amino]pyridine-4-yloxy}phenyl)-N'-(forfinal)malonamide

4-(4-Amino-2-pertenece)-2-[(morpholine-1-yl)carbylamine]pyridine (106 mg) was dissolved in N,N-dimethylformamide (2 ml) under nitrogen atmosphere and then added at 50°C N-(4-forfinal)malonic acid (189 mg), triethylamine (0,134 ml) and hexaflurophosphate (1H-1,2,3-benzotriazol-1 iloxi)[three(dimethylamino)]phosphonium (424 mg) followed by stirring at the same temperature for 1 hour and 30 minutes, the Reaction mixture was cooled to room temperature and distributed between ethyl acetate and 1 N. aqueous sodium hydroxide solution. The organic layer was washed with saturated aqueous sodium bicarbonate, water and saturated saline in this order, then dried over anhydrous sodium sulfate. The solvent is evaporated and get the remainder, which is purified column chromatography on silica gel (FUJI Silysia NH, eluent: ethyl acetate, then ethyl acetate:ethanol = 19:1). The fractions containing the spruce connection, concentrate and get the remainder, which is suspended in a mixture of diethyl ether (5 ml) - hexane (5 ml). The solid is filtered off, dried in the air flow and get listed in the title compound (116 mg, 70.6 per cent) in the form of white powder.

Range1H-NMR (DMSO-d6) δ (ppm): 3,37-to 3.41 (4H, m), 3,50 (2H, m), 3,52-of 3.60 (4H, m), 6,62 (1H, DD, J=2,4, 6,0 Hz), 7,17 (2H, m), 7,30 was 7.45 (3H, m), 7,63 (2H, DD, J=5,2, 8,8 Hz), 7,83 (1H, m)to 8.12 (1H, d, J=6.0 Hz), 9,29 (1H c), 10,27 (1H, Sirs), 10,52 (1H, Sirs).

Example 56

N-(4-Forfinal)-N'-(3-fluoro-4-{2-[(pyrrolidin-1-carbonyl)amino]pyridine-4-yloxy}phenyl)malonamide

4-(4-Amino-2-pertenece)-2-[(pyrrolidin-1-yl)carbylamine]pyridine (47,8 mg) dissolved in N,N-dimethylformamide (2 ml) under nitrogen atmosphere and then added at 50°C N-(4-forfinal)malonic acid (89,3 mg), triethylamine (0,063 ml) and hexaflurophosphate (1H-1,2,3-benzotriazol-1 iloxi)[three(dimethylamino)]phosphonium (200 mg) followed by stirring at the same temperature for 1 hour. The reaction mixture is cooled to room temperature, after which stirring is continued over night. The reaction mixture is distributed between ethyl acetate and 1 N. aqueous sodium hydroxide solution. The organic layer was washed with saturated aqueous sodium bicarbonate, water and saturated saline in this order, then dried over anhydrous sodium sulfate. The solvent upari is try and get the remainder, which is purified column chromatography on silica gel (FUJI Silysia NH, eluent: ethyl acetate, then ethyl acetate:ethanol = 5:5). The fractions containing the target compound, concentrate, and get the remainder, which is suspended in a mixture of diethyl ether-hexane (1:1). The solid is filtered off, dried in a stream of air, which is specified in the header of the connection (or 28.7 mg, 38.4 per cent) in the form of a powder pale yellow color.

Range1H-NMR (CDCl3) δ (ppm): 1,92 (4H, m), 3,39 (4H, m), 3,47 (2H, m), 6,74 (1H, d, J=2, 6,0 Hz), 6,90 (2H, m), 7,07 (1H, m), 7.23 percent (2H, m), 7,51 (2H, m), 7,56 (1H, m), a 7.62 (1H, d, J=10,8 Hz), of 8.09 (1H, d, J=6,0 Hz), 9,62 (1H, c), 10,08 (1H, Sirs).

Example 57

N-(3-Fluoro-4-{2-[(Pyrrolidin-1-carbonyl)amino]pyridine-4-yloxy}phenyl)-N'-(2,4-differenl)malonamide

4-(4-Amino-2-pertenece)-2-[pyrrolidin-1-yl)carbylamine]pyridine (50 mg) dissolved in N,N-dimethylformamide (2 ml) under nitrogen atmosphere and then added at 50°C N-(2,4-differenl)malonic acid (51,0 mg), triethylamine (0,033 ml) and hexaflurophosphate (1H-1,2,3-benzotriazol-1 iloxi)[three(dimethylamino)]phosphonium (105 mg), followed by stirring at the same temperature for 30 minutes, the Reaction mixture was cooled to room temperature and distributed between ethyl acetate and 1 N. aqueous sodium hydroxide solution. The organic layer was washed with saturated aqueous sodium bicarbonate, water and saturated saline solution pointed to by the m order then dried over anhydrous sodium sulfate. The solvent is evaporated and get the remainder, which is purified column chromatography on silica gel (FUJI Silysia NH, eluent: hexane:ethyl acetate = 1:1 to 1:3). The fractions containing the target compound, concentrate, and get the remainder, which is suspended in a mixture of diethyl ether-hexane (3:1), then the solid is filtered off. Then, the resulting solid is suspended in ethyl acetate (1 ml), filtered off and dried in a stream of air, getting mentioned in the title compound (12.5 mg, 15.4 per cent) in the form of a powder pale brown color.

Range1H-NMR (DMSO-d6) δ (ppm): 1,80 (4H, m), and 3.31 (4H, m)and 3.59 (2H, m), is 6.61 (1H, d, J=5.6 Hz), to 7.09 (1H, m), 7,20 was 7.45 (3H, m), 7,47 (1H, c), of 7.82 (1H, d, J=12,8 Hz), 7,94 (1H, DD, J=8,0, 15.2 Hz), 8,11 (1H, d, J=5,6 Hz), to 8.70 (1H, c), 10,06 (1H, m), 10,53 (1H, m).

Example 58

N-(2-Forfinal)-N'-(3-fluoro-4-{2-[(pyrrolidin-1-carbonyl)amino]pyridine-4-yloxy}phenyl)malonamide

N-(3-Fluoro-4-{2-[(pyrrolidin-1-carbonyl)amino]pyridine-4-yloxy}phenyl)malonic acid (20.0 mg) was dissolved in N,N-dimethylformamide (1 ml) under nitrogen atmosphere and then added at room temperature 2-forfinally (0,010 ml), triethylamine (0,014 ml) and hexaflurophosphate (1H-1,2,3-benzotriazol-1 iloxi)[three(dimethylamino)]phosphonium (44 mg), followed by stirring for 3 hours. The reaction mixture is distributed between ethyl acetate and saturated aqueous races is the thief of ammonium chloride. The organic layer was washed with saturated aqueous ammonium chloride, water and saturated saline in this order, then dried over anhydrous sodium sulfate. The solvent is evaporated and get the remainder, which is purified column chromatography on silica gel (eluent: hexane:ethyl acetate = 1:5, then ethyl acetate). The fractions containing the target compound, concentrate, and get the remainder, which is suspended in a mixture of diethyl ether (1 ml) - hexane (1 ml). The solid is filtered off, dried in the air flow and get listed in the title compound (15.3 mg, 62,1%) as white powder.

Range1H-NMR (DMSO-d6) δ (ppm): 1,80 (4H, m), 3,26-3,44 (4H, m), 3,61 (2H, c), 6,60 (1H, DD, J=2,4, 6,0 Hz), 7,10-of 7.23 (2H, m), 7.24 to to 7.32 (1H, m), 7,35 (1H, d, J=8,8 Hz), 7,39 (1H, m), 7,46 (1H, DD, J=2.0 Hz), 7,82 (1H, DD, J=2,4, of 12.8 Hz), to 7.99 (1H, m), 8,11 (1H, d, J=5.6 Hz), to 8.70 (1H, c), of 10.05 (1H, Sirs), 10,51 (1H, Sirs).

Example 59

N-(2,6-Differenl)-N'-(3-fluoro-4-{2-[(pyrrolidin-1-carbonyl)amino]pyridine-4-yloxy}phenyl)malonamide

N-(3-Fluoro-4-{2-[(pyrrolidin-1-carbonyl)amino]pyridine-4-yloxy}phenyl)malonic acid (20.0 mg) was dissolved in N,N-dimethylformamide (1 ml) under nitrogen atmosphere and then added at room temperature 2,6-dipertanyakan (0,010 ml), triethylamine (0,014 ml) and hexaflurophosphate (1H-1,2,3-benzotriazol-1 iloxi)[three(dimethylamino)]phosphonium (44 mg), followed by stirring for 3 h the owls. The reaction mixture is distributed between ethyl acetate and saturated aqueous ammonium chloride. The organic layer was washed with saturated aqueous ammonium chloride, water and saturated saline in this order, then dried over anhydrous sodium sulfate. The solvent is evaporated and get the remainder, which is purified column chromatography on silica gel (eluent: hexane:ethyl acetate = 1:5, then ethyl acetate). The fractions containing the target compound, concentrate, and get the remainder, which is suspended in a mixture of diethyl ether (1 ml) - hexane (1 ml). The solid is filtered off, dried in the air flow and get listed in the title compound (11.4 mg, 44.7 per cent) in the form of white powder.

Range1H-NMR (DMSO-d6) δ (ppm): 1,80 (4H, m), 3,26-of 3.42 (4H, m), of 3.56 (2H, c), 6,60 (1H, DD, J=2,4, 6,0 Hz), 7,18 (2H, m), 7,25-7,44 (3H, m), 7,47 (1H, d, J=2.4 Hz), 7,83 (1H, DD, J=2,4, 13,2 Hz), 8,10 (1H, d, J=6.0 Hz), to 8.70 (1H, m), 9,96 (1H, Sirs), 10,52 (1H, Sirs).

Example 60

N-(2-methoxyphenyl)-N'-(3-fluoro-4-{2-[(pyrrolidin-1-carbonyl)amino]pyridine-4-yloxy}phenyl)malonamide

N-(3-Fluoro-4-{2-[(pyrrolidin-1-carbonyl)amino]pyridine-4-yloxy}phenyl)malonic acid (20.0 mg) was dissolved in N,N-dimethylformamide (1 ml) under nitrogen atmosphere and then added at room temperature 2-methoxybenzylamine (0,011 ml), triethylamine (0,014 ml) and hexaflurophosphate (1H-1,2,3-benzotriazol-1 iloxi)[three(dimate is amino)]phosphonium (44 mg) followed by stirring for 30 minutes The reaction mixture is distributed between ethyl acetate and saturated aqueous ammonium chloride. The organic layer was washed with saturated aqueous ammonium chloride, water and saturated saline in this order, then dried over anhydrous sodium sulfate. The solvent is evaporated and get the remainder, which is purified column chromatography on silica gel (FUJI Silysia NH, eluent: hexane:ethyl acetate = 1:5, then ethyl acetate). The fractions containing the target compound, concentrate, and get the remainder, which is suspended in a mixture of diethyl ether (1 ml) - hexane (1 ml). The solid is filtered off, dried in a stream of air, which is specified in the header connection (15,0 mg, 59.1 per cent) in the form of white powder.

Range1H-NMR (CDCl3) δ (ppm): 1,95 (4H, m), 3,44 (4H, m), 3,55 (2H, Sirs), 3,90 (3H, c), 6,56 (1H, DD, J=2,4, 5,6 Hz), make 6.90 (1H, DD, J=1,2, 8.0 Hz), 6,99 (1H, m), 7,01 (1H, Sirs), 7,05-to 7.18 (2H, m), 7.23 percent (1H, m), of 7.69 (1H, d, J=2.4 Hz), of 7.75 (1H, DD, J=2,8, 12 Hz), with 8.05 (1H, d, J=6.0 Hz), 8,31 (1H, DD, J=1,6, 8.0 Hz), 8,54 (1H, Sirs), for 9.64 (1H, Sirs).

Example 61

N-Cycloheptyl-N'-(3-fluoro-4-{2-[(pyrrolidin-1-carbonyl)amino]pyridine-4-yloxy}phenyl)malonamide

N-(3-Fluoro-4-{2-[(pyrrolidin-1-carbonyl)amino]pyridine-4-yloxy}phenyl)malonic acid (20,8 mg) dissolved in N,N-dimethylformamide (1 ml) under nitrogen atmosphere and then added at room temperature cycloheptylamine (0,010 ml), triethylamine (0,014 ml)and hexaflurophosphate (1H-1,2,3-benzotriazol-1 iloxi)[three(dimethylamino)]phosphonium (46 mg), followed by stirring for 30 minutes The reaction mixture is distributed between ethyl acetate and saturated aqueous ammonium chloride. The organic layer was washed with saturated aqueous ammonium chloride, water and saturated saline in this order, then dried over anhydrous sodium sulfate. The solvent is evaporated and get the remainder, which is purified column chromatography on silica gel (eluent: hexane:ethyl acetate = 1:5, then ethyl acetate). The fractions containing the target compound, concentrate, and get the remainder, which is suspended in a mixture of diethyl ether (1 ml) - hexane (1 ml). The solid is filtered off, dried in the air flow and get listed in the title compound (19.7 mg, 76.6 per cent) in the form of white powder.

Range1H-NMR (CDCl3) δ (ppm): 1,40-of 1.74 (10H, m), of 1.95 (6H, m), or 3.28 (2H, c), 3,44 (4H, m)to 3.99 (1H, m), 6,16 (1H, m), is 6.54 (1H, DD, J=2,4, 6,0 Hz), 7,03 (1H, Sirs), 7,12 (1H, m), 7,22 (1H, m), to 7.67 (1H, d, J=2.4 Hz), 7,73 (1H, DD, J=2,4, 12 Hz), 8,03 (1H, d, J=6.0 Hz), 9,85 (1H, Sirs).

Example 62

N-(2-Chloro-4-{2-[(Morpholine-4-carbonyl)amino]pyridine-4-yloxy}phenyl)-N'-(4-forfinal)malonamide

Morpholine-4-carboxylic acid [4-(4-amino-3-chlorophenoxy)pyridine-2-yl]amide (93,2 mg) dissolved in N,N-dimethylformamide (2 ml) under nitrogen atmosphere and then added at 50°C N-(4-forfinal)malonic acid (105 mg), triethylamine (0,074 ml) and hexaflurophosphate (1H-1,2,3-benzotriazol-1 iloxi)[three(dimethylamino)]FOS is one (236 mg), followed by stirring at the same temperature for 1 hour. To the reaction mixture add another portion of N-(4-forfinal)malonic acid (and 62.6 mg), triethylamine (0,027 ml) and hexaflurophosphate (1H-1,2,3-benzotriazol-1 iloxi)[three(dimethylamino)]phosphonium (118 mg), followed by stirring for 2 hours and 45 minutes, the Reaction mixture was cooled to room temperature and distributed between ethyl acetate and 1 N. aqueous sodium hydroxide solution. The organic layer was washed with saturated aqueous sodium bicarbonate, water and saturated saline in this order, then dried over anhydrous sodium sulfate. The solvent is evaporated and get the remainder, which is purified column chromatography on silica gel (FUJI Silysia NH, eluent: hexane:ethyl acetate = 1:3). The fractions containing the target compound, concentrate, and get the remainder, to which is added a mixture of hexane (20 ml) - ethyl acetate (2 ml)to precipitate crystals. The crystals are filtered and dried in a stream of air, getting mentioned in the title compound (77,1 mg, 54.7 per cent) in the form of white crystals.

Range1H-NMR (DMSO-d6) δ (ppm): 3,36-3,44 (4H, m), 3,55 (4H, m), 3,61 (2H, m), 6,63 (1H, m), 7,17 (3H, m), 7,41 (2H, m), a 7.62 (2H, m), to 7.99 (1H, m), 8,14 (1H, m), 9,31 (1H, Sirs), 10,06 (1H, Sirs), 10,31 (1H, Sirs).

Example 63

N-(4-Forfinal)-N'-[2-chloro-4-(2-{[(4-pyrrolidin-1-yl)piperidine-1-carbonyl]amino}pyridine-4-yloxy)phenyl]malonamic

4-(Pyrrolidin-1-yl)piperidine-1-ka is oil acid [4-(4-amino-3-chlorophenoxy)pyridine-2-yl]amide (129 mg) was dissolved in N,N-dimethylformamide (2 ml) under nitrogen atmosphere and then added at 50° C N-(4-forfinal)malonic acid (183 mg), triethylamine (0,130 ml) and hexaflurophosphate (1H-1,2,3-benzotriazol-1 iloxi)[three(dimethylamino)]phosphonium (411 mg), followed by stirring at the same temperature for 5 hours and 30 minutes, the Reaction mixture was cooled to room temperature, followed by stirring for 2 days. The reaction mixture is distributed between ethyl acetate and 1 N. aqueous sodium hydroxide solution. The organic layer was washed with saturated aqueous sodium bicarbonate, water and saturated saline in this order, then dried over anhydrous sodium sulfate. The solvent is evaporated and get the remainder, which is purified column chromatography on silica gel (FUJI Silysia NH, eluent: ethyl acetate:ethanol = 19:1). The fractions containing the target compound, concentrate, and get the remainder, to which is added diethyl ether to precipitate crystals. The crystals are filtered and dried in a stream of air, getting mentioned in the title compound, or 64.7 mg, 35.1 per cent) in the form of white crystals.

Range1H-NMR (DMSO-d6) δ (ppm): 1,09 (2H, t, J=7 Hz), 1,20-of 1.35 (2H, m), of 1.65 (4H, m), of 1.78 (2H, m), 2,12 (1H, m), 2,46 (2H, m), of 2.86 (2H, m), 3,61 (2H, Sirs), of 3.97 (2H, m), 6,32 (1H, DD, J=2.0 a, 6,0 Hz), 7,10-of 7.25 (3H, m), 7,41 (2H, m), 7,63 (2H, m), to 7.99 (1H, m), 8,13 (1H, d, J=6.0 Hz), of 9.21 (1H, c), 10,06 (1H, Sirs), 10,31 (1H, Sirs).

Example 64

N-(2-Chloro-4-{2-[(azetidin-1-carbonyl)amino]PI is one-4-yloxy}phenyl)-N'-(4-forfinal)malonamide

Azetidin-1-carboxylic acid [4-(4-amino-3-chlorophenoxy)pyridine-2-yl]amide (100 mg) dissolved in N,N-dimethylformamide (2 ml) under nitrogen atmosphere and then added at 50°C N-(4-forfinal)malonic acid (186 mg), triethylamine (0,131 ml) and hexaflurophosphate (1H-1,2,3-benzotriazol-1 iloxi)[three(dimethylamino)]phosphonium (417 mg) followed by stirring at the same temperature for 1 hour. The reaction mixture is cooled to room temperature and distributed between ethyl acetate and 1 N. aqueous sodium hydroxide solution. The organic layer was washed with saturated aqueous sodium bicarbonate, water and saturated saline in this order, then dried over anhydrous sodium sulfate. The solvent is evaporated, obtaining a residue which is suspended in diethyl ether. The solid is filtered off, dried in the air flow and get listed in the title compound (128 mg, 81.7 per cent) in the form of a powder pale brown color.

Range1H-NMR (DMSO-d6) δ (ppm): 2,08-of 2.20 (2H, m), 3,61 (2H, m), of 3.94 (4H, m), 6,60 (1H, DD, J=2,4, 6,0 Hz), 7,14-of 7.25 (3H, m), 7,42 (1H, d, J=2,8 Hz), 7,51 (1H, d, J=2.4 Hz), 7,63 (2H, m), 8,00 (1H, m)to 8.12 (1H, d, J=6,0 Hz), 9,10 (1H, Sirs), of 10.05 (1H, Sirs), 10,30 (1H, Sirs).

Example 65

N-(2-Chloro-4-{2-[(piperidine-1-carbonyl)amino]pyridine-4-yloxy}phenyl)-N'-(4-forfinal)malonamide

Piperidine-1-carboxylic acid [4-(4-amino-3-chlorophenoxy)pyridine-2-yl]amide (10 mg) dissolved in N,N-dimethylformamide (2 ml) under nitrogen atmosphere and then added at 50° C N-(4-forfinal)malonic acid (171 mg), triethylamine (0,121 ml) and hexaflurophosphate (1H-1,2,3-benzotriazol-1 iloxi)[three(dimethylamino)]phosphonium (383 mg), followed by stirring at the same temperature for 1 hour and 30 minutes, the Reaction mixture was cooled to room temperature and distributed between ethyl acetate and 1 N. aqueous sodium hydroxide solution. The organic layer was washed with saturated aqueous sodium bicarbonate, water and saturated saline in this order, then dried over anhydrous sodium sulfate. The solvent is evaporated, receiving the remnant that purify column chromatography on silica gel (FUJI Silysia NH, eluent: ethyl acetate:ethanol = 49:1). The fractions containing the crude product, concentrate, receiving the remainder, which is then purified column chromatography on silica gel (FUJI Silysia NH, eluent: ethyl acetate:ethanol = 49:1). The fractions containing the target compound, concentrate, and get the remainder, which is suspended in a mixture of diethyl ether (5 ml) - hexane (5 ml). The solid is filtered off, dried in the air flow and get listed in the title compound (123 mg, 81,3%) as white powder.

Range1H-NMR (DMSO-d6) δ (ppm): 0,86 (2H, m), 1,24 (2H, m)of 1.45 (4H, m), and 1.54 (2H, m), 3,61 (2H, m), 6,60 (1H, DD, J=2.0 a, 6,0 Hz), 7,14-of 7.25 (3H, m), 7,35-7,45 (2H, m), 7,63 (2H, DD, J=5,2, 9,2 Hz), to 7.99 (1H, d, J=9,2 Hz), 8,13 (1H, d, J=6.0 G is), 9,16 (1H, c), 10,06 (1H, Sirs), 10,31 (1H, Sirs).

Example 66

N-(2-Chloro-4-{2-[(pyrrolidin-1-carbonyl)amino]pyridine-4-yloxy}phenyl)-N'-(4-forfinal)malonamide

Pyrrolidin-1-carboxylic acid [4-(4-amino-3-chlorophenoxy)pyridine-2-yl]amide (to 79.6 mg) dissolved in N,N-dimethylformamide (1.5 ml) under nitrogen atmosphere and then added at 50°C N-(4-forfinal)malonic acid (142 mg), triethylamine (0.100 ml) and hexaflurophosphate (1H-1,2,3-benzotriazol-1 iloxi)[three(dimethylamino)]phosphonium (318 mg), followed by stirring at the same temperature for 2 hours and 30 minutes, the Reaction mixture was cooled to room temperature and distributed between ethyl acetate and 1 N. aqueous sodium hydroxide solution. The organic layer was washed with saturated aqueous sodium bicarbonate, water and saturated saline in this order, then dried over anhydrous sodium sulfate. The solvent is evaporated and get the remainder, which is purified column chromatography on silica gel (eluent: ethyl acetate). The fractions containing the target compound, concentrate, and get the remainder, which is suspended in a mixture of diethyl ether (5 ml) - hexane (5 ml). The solid is filtered off, dried in a stream of air, which is specified in the header of the connection (or 94.5 mg, 76,9%) as white powder.

Range1H-NMR (DMSO-d6) δ (ppm): is 1.81 (4H, m), 3.27 to of 3.42 (4H, m, 3,61 (2H, m), is 6.61 (1H, DD, J=2,4, 5,6 Hz), 7,15-of 7.25 (3H, m), 7,42 (1H, d, J=2,8 Hz), 7,51 (1H, d, J=2.4 Hz), 7,63 (2H, DD, J=4,8, 8,8 Hz), 8,00 (1H, d, J=8,8 Hz), 8,13 (1H, d, J=5.6 Hz), 8,72 (1H, c), of 10.05 (1H, c), 10,31 (1H, Sirs).

Example 67

N-(3-Chloro-4-{2-[(Pyrrolidin-1-carbonyl)amino]pyridine-4-yloxy}phenyl)-N'-(4-forfinal)malonamide

4-(4-Amino-2-chlorophenoxy)-2-[(pyrrolidin-1-yl)carbylamine]pyridine (99 mg) was dissolved in N,N-dimethylformamide (2 ml) under nitrogen atmosphere and then added at 50°C N-(4-forfinal)malonic acid (176 mg), triethylamine (0,124 ml) and hexaflurophosphate (1H-1,2,3-benzotriazol-1 iloxi)[three(dimethylamino)]phosphonium (394 mg) followed by stirring at the same temperature for 30 minutes, the Reaction mixture was cooled to room temperature and distributed between ethyl acetate and 1 N. aqueous sodium hydroxide solution. The organic layer was washed with saturated aqueous sodium bicarbonate, water and saturated saline in this order, then dried over anhydrous sodium sulfate. The solvent is evaporated and get the remainder, which is purified column chromatography on silica gel (FUJI Silysia NH, eluent: ethyl acetate, then ethyl acetate:ethanol = 95:5). The fractions containing the target compound, concentrate, and get the remainder, which is suspended in diethyl ether. The solid is filtered off, dried in a stream of air, which is specified in the header link is (to 102.9 mg, 67,7%) as white powder.

Range1H-NMR (CDCl3) δ (ppm): of 1.65 (4H, m), 3,32-3,44 (4H, m), of 3.46 (2H, m), 6,74 (1H, DD, J=2,4, 5,6 Hz), 6,92 (2H, m), 7,11 (2H, d, J=8,8 Hz), 7,40-EUR 7.57 (4H, m), 7,74 (1H, d, J=2.4 Hz), 8,11 (1H, d, J=5.6 Hz), 9,41 (1H, Sirs), 9,92 (1H, Sirs).

Example 68

N-(3-Chloro-4-{2-[(morpholine-4-carbonyl)amino]pyridine-4-yloxy}phenyl)-N'-(4-forfinal)malonamide

4-(4-Amino-2-chlorophenoxy)-2-[(morpholine-1-yl)carbylamine]pyridine (119 mg) was dissolved in N,N-dimethylformamide (2 ml) under nitrogen atmosphere and then added at 50°C N-(4-forfinal)malonic acid (202 mg), triethylamine (0,143 ml) and hexaflurophosphate (1H-1,2,3-benzotriazol-1 iloxi)[three(dimethylamino)]phosphonium (452 mg) followed by stirring at the same temperature for 30 minutes, the Reaction mixture was cooled to room temperature and distributed between ethyl acetate and 1 N. aqueous sodium hydroxide solution. The organic layer was washed with saturated aqueous sodium bicarbonate, water and saturated saline in this order, then dried over anhydrous sodium sulfate. The solvent is evaporated and get the remainder, which is purified column chromatography on silica gel (FUJI Silysia NH, eluent: ethyl acetate, then ethyl acetate:ethanol = 19:1). The fractions containing the target compound, concentrate, and get the remainder, to which is added a mixture of diethyl ether-hexane (1:1)to precipitate kristallichnosti filtered and dried in a stream of air, getting listed in the title compound (106,1 mg, 58,9%) as white crystals.

Range1H-NMR (DMSO-d6) δ (ppm): 3,39 (4H, m), 3,50 (2H, m), 3,55 (4H, m), to 6.57 (1H, DD, J=2,4, 6,0 Hz), 7,17 (2H, m), 7,32 (2H, m), 7,56 (1H, DD, J=2,4, 8,8 Hz), 7,63 (2H, m), 8,01 (1H, d, J=2.4 Hz), to 8.12 (1H, d, J=6,0 Hz), 9,27 (1H, c), 10,27 (1H, Sirs), 10,50 (1H, Sirs).

Example 69

N-(4-Forfinal)-N'-(4-{2-[(pyrrolidin-1-carbonyl)amino]pyridine-4-yloxy}phenyl)malonamide

4-(4-Aminophenoxy)-2-[(pyrrolidin-1-yl)carbylamine]pyridine (30 mg) dissolved in N,N-dimethylformamide (1 ml) under nitrogen atmosphere and then added at 50°C N-(4-forfinal)malonic acid (59,5 mg), triethylamine (0,042 ml) and hexaflurophosphate (1H-1,2,3-benzotriazol-1 iloxi)[three(dimethylamino)]phosphonium (134 mg), followed by stirring at the same temperature in for 30 minutes the Reaction mixture is cooled to room temperature and distributed between ethyl acetate and 1 N. aqueous sodium hydroxide solution. The organic layer was washed with saturated aqueous sodium bicarbonate, saturated aqueous ammonium chloride, water and saturated saline in this order, then dried over anhydrous sodium sulfate. The solvent is evaporated and get the remainder, which is purified column chromatography on silica gel (eluent: hexane:ethyl acetate = 1:5, then ethyl acetate). The fractions containing the target compound, concenterate get the rest, which are suspended in a mixture of diethyl ether (2 ml) - hexane (2 ml). The solid is filtered off, dried in a stream of air, which is specified in the header connection (40,4 mg of 83.4%) as a solid pale brown color.

Range1H-NMR (DMSO-d6) δ (ppm): 1,80 (4H, m), 3,30 is 3.40 (4H, m), of 3.48 (2H, m), 6,56 (1H, DD, J=2,4, 5,6 Hz), to 7.15 (4H, m), 7,46 (1H, d, J=2.0 Hz), 7,63 (2H, DD, J=5,2, 8,8 Hz), 7,69 (2H, d, J=9,2 Hz), of 8.09 (1H, c), 8,65 (1H, c), of 10.25 (1H, m), 10,31 (1H, c).

Example 70

N-{4-[2-(3,3-Dimethylurea)pyridine-4-yloxy]phenyl}-N'-(4-forfinal)malonamide

1-[4-(4-Aminophenoxy)pyridine-2-yl]-3,3-dimethyloxetane (30 mg) dissolved in N,N-dimethylformamide (1 ml) under nitrogen atmosphere and then added at 50°C N-(4-forfinal)malonic acid (65,1 mg), triethylamine (0,046 ml) and hexaflurophosphate (1H-1,2,3-benzotriazol-1 iloxi)[three(dimethylamino)]phosphonium (146 mg), followed by stirring at the same temperature for 1.5 hours. The reaction mixture is cooled to room temperature and distributed between ethyl acetate and 1 N. aqueous sodium hydroxide solution. The organic layer was washed with saturated aqueous sodium bicarbonate, saturated aqueous ammonium chloride, water and saturated saline in this order, then dried over anhydrous sodium sulfate. The solvent is evaporated and get the remainder, which is purified column chromatography on when likehere (FUJI Silysia NH, eluent: hexane:ethyl acetate = 1:5-1:8). The fractions containing the target compound, concentrate, and get the remainder, which is suspended in a mixture of diethyl ether (2 ml) - hexane (2 ml). The solid is filtered off, dried in a stream of air, which is specified in the header connection (to 43.4 mg, 87.4 per cent) in the form of a solid white color.

Range1H-NMR (DMSO-d6) δ (ppm): 2,89 (6H, c), of 3.48 (2H, c), 6,56 (1H, DD, J=2,8, 6,0 Hz), to 7.15 (4H, m), 7,37 (1H, d, J=2.0 Hz), 7,63 (2H, DD, J=5,2, 9,2 Hz), 7,69 (2H, d, J=9,2 Hz), of 8.09 (1H, d, J=6.0 Hz), cent to 8.85 (1H, c), 10,26 (1H, c), 10,31 (1H, c).

Example 71

N-(4-Forfinal)-N'-(4-{2-[(morpholine-4-carbonyl)amino]pyridine-4-yloxy}phenyl)malonamide

4-(4-Aminophenoxy)-2-[(morpholine-1-yl)carbylamine]pyridine (30 mg) dissolved in N,N-dimethylformamide (1 ml) under nitrogen atmosphere and then added at room temperature N-(4-forfinal)malonic acid (30.0 mg), triethylamine (0,027 ml) and hexaflurophosphate (1H-1,2,3-benzotriazol-1 iloxi)[three(dimethylamino)]phosphonium (85 mg), followed by stirring overnight. The reaction mixture is cooled to room temperature and distributed between ethyl acetate and 1 N. aqueous sodium hydroxide solution. The organic layer was washed with saturated aqueous sodium bicarbonate, saturated aqueous ammonium chloride, water and saturated saline in this order, then dried over anhydrous sulfate intothree is. The solvent is evaporated and get the remainder, which is purified column chromatography on silica gel (FUJI Silysia NH, eluent: hexane:ethyl acetate = 1:3, then ethyl acetate). The fractions containing the target compound, concentrate, and get the remainder, which is suspended in a mixture of diethyl ether (1 ml) - hexane (1 ml). The solid is filtered off, dried in a stream of air, which is specified in the header connection (45,9 mg, 97,5%) as a solid pale brown color.

Range1H-NMR (DMSO-d6) δ (ppm): 3.40 in (4H, m), 3,47 (2H, c), 3,55 (4H, m), to 6.58 (1H, DD, J=2,4, 6,0 Hz), 7,08-7,24 (4H, m), 7,35 (1H, d, J=2.4 Hz), 7,58-7,66 (2H, m), of 7.70 (2H, d, J=2.4 Hz), 8,11 (1H, d, J=6.0 Hz), 9,23 (1H, Sirs), of 10.25 (1H, Sirs), 10,31 (1H, Sirs).

Example 72

N-(4-Forfinal)-N'-[3-fluoro-4-(2-{[4-(pyrrolidin-1-yl)piperidine-1-yl]carbylamine}pyridine-4-yloxy)phenyl]malonamic

4-(4-Amino-2-pertenece)-2-{[4-(pyrrolidin-1-yl)carbylamine}pyridine (78,6 mg) dissolved in N,N-dimethylformamide (2 ml) under nitrogen atmosphere and then added at room temperature N-(4-forfinal)malonic acid (77,6 mg), triethylamine (by 0.055 ml) and hexaflurophosphate (1H-1,2,3-benzotriazol-1 iloxi)[three(dimethylamino)]phosphonium (174 mg), followed by stirring for 2 hours. The reaction mixture is distributed between ethyl acetate and saturated aqueous sodium bicarbonate. The organic layer is washed with water and saturated salt rastv the rum in this order, then dried over anhydrous sodium sulfate. The solvent is evaporated and get the remainder, which is purified column chromatography on silica gel (FUJI Silysia NH, eluent: ethyl acetate, then ethyl acetate:methanol = 95:5 to 9:1). The fractions containing the target compound, concentrate, and get the remainder, which is suspended in a mixture of ethyl acetate/hexane (1/5). The solid is filtered off, dried in a stream of air, which is specified in the header connection (33.3 mg, 29%) as a powder pale pink color.

Range1H-NMR (DMSO-d6) δ (ppm): 1,20-1,40 (2H, m), 1,60-1,70 (4H, m), 1,70-1,80 (2H, m), 2,12 (1H, m), 2,40-2,60 (4H, m), of 2.86 (2H, m), 3,50 (2H, c), 3,90-of 4.05 (2H, m), 6,59 (1H, DD, J=2,4, 5,6 Hz), 7,16 (2H, m), 7,30-7,40 (3H, m), 7,60-of 7.70 (2H, m), 7,82 (1H, m), 8,11 (1H, d, J=5.6 Hz), 9,19 (1H, c), 10,26 (1H, c), 10,51 (1H, c).

Example 73

N-(4-Forfinal)-N'-[4-{[2-(dimethylamino)carbylamine]pyridine-4-yloxy}-3-forfinal)malonamide

4-(4-Amino-2-pertenece)-2-[(dimethylamino)carbylamine]pyridine (22 mg) was dissolved in N,N-dimethylformamide (1 ml) under nitrogen atmosphere and then added at room temperature N-(4-forfinal)malonic acid (45 mg), triethylamine (0,032 ml) and hexaflurophosphate (1H-1,2,3-benzotriazol-1 iloxi)[three(dimethylamino)]phosphonium (100 mg), followed by stirring at 50°C for 1.5 hours. The reaction mixture is distributed between ethyl acetate and saturated aqueous sodium bicarbonate. Organicheskikh washed with saturated aqueous sodium hydrogen carbonate, water and saturated saline in this order, then dried over anhydrous sodium sulfate. The solvent is evaporated and get the remainder, which is purified column chromatography on silica gel (eluent: ethyl acetate, then ethyl acetate:methanol = 9:1). The fractions containing the target compound, concentrate, and get the remainder, which is suspended in a mixture of diethyl ether/hexane (1/2). The solid is filtered off, dried in the air flow and get listed in the title compound (29 mg, 82%) as white powder.

Range1H-NMR (CDCl3) δ (ppm): 3,00 (6H, c), 3,47 (2H, c), of 6.66 (1H, DD, J=2,4, 6,0 Hz), of 6.96-7,01 (2H, m), 7,11 (1H, m), 7,20-7,30 (2H, m), 7,50-rate of 7.54 (2H, m), 7,56 (1H, d, J=2.4 Hz), to 7.67 (1H, DD, J=2,4, 12.0 Hz), 8,08 (1H, d, J=6.0 Hz), 9,03 (1H, c), at 9.53 (1H, c).

Example 74

N-(4-Forfinal)-N'-[4-(2-acetylpiperidine-4-yloxy)-2-forfinal]malonamic

N-(4-Forfinal)-N'-[4-(2-aminopyridine-4-yloxy)-2-forfinal]malonamide (20.6 mg) dissolved in N,N-dimethylformamide (0.5 ml) and then in a nitrogen atmosphere at room temperature was added drop wise addition of triethylamine (0,043 ml) and acetylchloride (0,011 ml), followed by stirring overnight. To the reaction mixture add 1 N. aqueous sodium hydroxide solution (1.5 ml), stirred and extracted with ethyl acetate. The organic layer is concentrated under reduced pressure, obtaining a residue, which is purified column chromatographia silica gel (FUJI Silysia NH, eluent: ethyl acetate). The fractions containing the target compound, concentrate, and get the remainder, which is then dried in vacuum, obtaining mentioned in the title compound (9.3 mg, 41%) as white powder.

Range1H-NMR (CDCl3) δ (ppm): 2,17 (3H, c), of 3.60 (2H, c), 6,62 (1H, DD, J=2,4, 5,6 Hz), 6,88-6,93 (2H, m), 7,00-7,05 (2H, m), 7,51-7,56 (2H, m), 7,80 (1H, c)to 8.12 (1H, d, J=5.6 Hz), 8,24 (1H, m), 8,35 (1H, m), 9,04 (1H, Sirs), which 9.22 (1H, Sirs).

Example 75

N-(4-Forfinal)-N'-[4-(2-propiomelanocortin-4-yloxy)-2-forfinal]malonamic

N-(4-Forfinal)-N'-[4-(2-aminopyridine-4-yloxy)-2-forfinal]malonamide (20.2 mg) dissolved in N,N-dimethylformamide (0.5 ml) and then in a nitrogen atmosphere at room temperature was added drop wise addition of triethylamine (0,042 ml) and propionitrile (0,013 ml), followed by stirring overnight. To the reaction mixture add 1 N. aqueous sodium hydroxide solution (1.5 ml), stirred and extracted with ethyl acetate. The organic layer is concentrated under reduced pressure, obtaining a residue, which is purified column chromatography on silica gel (FUJI Silysia NH, eluent: ethyl acetate). The fractions containing the target compound, concentrate, and get the remainder, which is then dried in vacuum, obtaining mentioned in the title compound (9.0 mg, 39%) as a powder pale yellow color.

Range1H-NMR (CDCl3) δ (ppm): to 1.21 (3H, t, J=7,6 Hz), 2.40 a (2H, q, J=7,6 Hz)to 3.58 (2H, c), 6,62 (1H, m, 6,89-6,92 (2H, m), 7,00-7,05 (2H, m), 7,50-EUR 7.57 (2H, m), 7,81 (1H, c), 8,00-to 8.20 (2H, m), of 8.25 (1H, m), of 8.90 (1H, Sirs), 9,11 (1H, Sirs).

Example 76

N-(4-Forfinal)-N'-[4-(2-isobutyleneisoprene-4-yloxy)-2-forfinal]malonamic

N-(4-Forfinal)-N'-[4-(2-aminopyridine-4-yloxy)-2-forfinal]malonamide (20,1 mg) dissolved in N,N-dimethylformamide (0.5 ml) and then in a nitrogen atmosphere at room temperature was added drop wise addition of triethylamine (0,040 ml) and isobutyrate (0,008 ml) followed by stirring for 1 hour. To the reaction mixture add 1 N. aqueous sodium hydroxide solution (1.0 ml), stirred and extracted with ethyl acetate. The organic layer is concentrated under reduced pressure, obtaining a residue, which is purified column chromatography on silica gel (FUJI Silysia NH, eluent: ethyl acetate). The fractions containing the target compound, concentrate, and get the remainder, which is then dried in vacuum, obtaining mentioned in the title compound (11.7 mg, 49%) as a powder pale yellow color.

Range1H-NMR (CDCl3) δ (ppm): to 1.21 (3H, d, J=6,8 Hz)of 1.23 (3H, d, J=6.8 Hz), 2,53 (1H, m), of 3.60 (2H, c), only 6.64 (1H, DD, J=2.0 a, and 3.2 Hz), 6.89 in-6,92 (2H, m), 7,00? 7.04 baby mortality (2H, m), 7,40-of 7.60 (2H, m), 7,82 (1H, c), 8,00-to 8.20 (2H,, m)of 8.25 (1H, m), 9,07 (1H, Sirs), 9,23 (1H, Sirs).

Example 77

N-(4-Forfinal)-N'-{4-[2-(cyclopropanecarbonyl)pyridine-4-yloxy]-2-forfinal}malonamic

N-(4-Forfinal)-N'-[4-(2-aminopyridine-4-yloxy)-2-forfinal]malonamide (21,3 mg) is dissolved in NN-dimethylformamide (0.5 ml) and then in a nitrogen atmosphere at room temperature was added drop wise addition of triethylamine (0,030 ml) and cyclopropanecarbonitrile (0,010 ml) followed by stirring for 1 hour. To the reaction mixture add 1 N. aqueous sodium hydroxide solution (1.0 ml) and methanol (1.0 ml), stirred and extracted with ethyl acetate. The organic layer is concentrated under reduced pressure, obtaining a residue, which is purified column chromatography on silica gel (FUJI Silysia NH, eluent: ethyl acetate). The fractions containing the target compound, concentrate, and get the remainder, which is then dried in vacuum, obtaining mentioned in the title compound (9.6 mg, 39%) as white powder.

Range1H-NMR (CDCl3) δ (ppm): 0,80-1,60 (5H, m), of 3.56 (2H, c), is 6.61 (1H, m), 6,93-was 7.08 (4H, m), 7,50-of 7.55 (2H, m), 7,79 (1H, c), 8,12-8,17 (2H, m), of 8.28 (1H, m), to 8.57 (1H, m), 8,79 (1H, m).

Example 78

N-(4-Forfinal)-N'-{2-fluoro-4-[({[4-(piperidine-1-yl)piperidine-1-yl]carbonyl}amino)pyridine-4-yloxy]phenyl}malonamic

N-(4-Forfinal)-N'-[4-(2-aminopyridine-4-yloxy)-2-forfinal]malonamic in (17.0 mg) dissolved in tetrahydrofuran (1.0 ml) and then in a nitrogen atmosphere at room temperature was added drop wise addition of triethylamine (0,015 ml) and phenylcarbamate (0,013 ml) followed by stirring for 30 minutes the Reaction mixture was concentrated under reduced pressure, obtaining a residue which is then dissolved in N,N-dimethylformamide (0.5 ml). At room temperature is added 4-(piperidine-1-yl)piperidine (80 mg) and stirred for 23 hours. The reaction mixture is distributed between ethyl acetate and water. Org the organic layer washed with water, saturated aqueous ammonium chloride and saturated saline in this order, then dried over anhydrous sodium sulfate. The solvent is evaporated, obtaining a residue, to which is added ethyl acetate (2.5 ml)to precipitate crystals. The crystals are filtered and dried in a stream of air, getting mentioned in the title compound (10.4 mg, 41%) as white crystals.

Range1H-NMR (DMSO-d6) δ (ppm): 1,20-3,50 (17H, m)and 3.59 (2H, c), 4,20-4,30 (2H, m), only 6.64 (1H, m), 7,01 (1H, d, J=8,8 Hz), 7,15-7,27 (3H, m), 7,40 (1H, c), 7,50-of 7.70 (2H, m), 8,03 (1H, m), 8,15 (1H, m), 9,39 (1H, Sirs), 10,13 (1H, Sirs), 10,32 (1H, Sirs).

Example 79

N-(4-Forfinal)-N'-{4-[2-(cyclopropanecarbonyl)pyridine-4-yloxy]-3-forfinal}malonamic

N-(4-Forfinal)-N'-[4-(2-aminopyridine-4-yloxy)-3-forfinal]malonamide (34 mg) was dissolved in N,N-dimethylformamide (0.5 ml) and then in a nitrogen atmosphere at room temperature was added drop wise addition of triethylamine (0,047 ml) and cyclopropanecarbonitrile (0,016 ml) followed by stirring for 1 hour. To the reaction mixture add 1 N. aqueous sodium hydroxide solution (1.5 ml) and methanol (1.0 ml), stirred and extracted with ethyl acetate. The organic layer is washed with water and saturated aqueous solution of ammonium chloride in this order, then dried over anhydrous sodium sulfate. The solvent is evaporated and get the remainder, which is clear to Nochnoi chromatography on silica gel (FUJI Silysia NH, eluent: ethyl acetate). The fractions containing the target compound, concentrate, and get the remainder, which is then dried in vacuum, obtaining mentioned in the title compound (21.1 mg, 53%) as white powder.

Range1H-NMR (CDCl3) δ (ppm): 0,80-1,60 (5H, m), 3,52 (2H, c), only 6.64 (1H, m), 7,01-7,26 (4H, m), 7,50-of 7.55 (2H, m), 7,70-7,80 (2H, m)to 8.12 (1H, d, J=5.6 Hz), by 8.22 (1H, c), a total of 8.74 (1H, c), of 9.30 (1H, c).

Example 80

N-(2-Fluoro-4-{2-[(morpholine-4-carbonyl)amino]pyridine-4-yloxy}phenyl)-N'-(4-forfinal)malonamide

To a solution of morpholine-4-carboxylic acid [4-(4-amino-3-pertenece)pyridine-2-yl]amide (48 mg) in N,N-dimethylformamide (3.0 ml) is added N-(4-forfinal)malonic acid (48 mg) and hexaphosphate benzotriazol-1-yloxytris(dimethylamino)phosphonium (96 mg), followed by stirring at 50°C for 2.5 hours and at room temperature for 56 hours. Add N-(4-forfinal)malonic acid (48 mg) and hexaflurophosphate (1H-1,2,3-benzotriazol-1 iloxi)[three(dimethylamino)]phosphonium (96 mg) and stirred at 50°C for 2 hours. The reaction mixture is cooled to room temperature and stirred for another 3.3 hours. Add another portion of N-(4-forfinal)malonic acid (48 mg) and hexaflurophosphate (1H-1,2,3-benzotriazol-1 iloxi)[three(dimethylamino)]phosphonium (96 mg) and stirred at 50°C for 2.5 hours. The reaction mixture is distributed between ethyl acetate (100 ml) and neymann the m aqueous solution of sodium bicarbonate (100 ml). The organic layer was washed with saturated saline and dried over anhydrous sodium sulfate. The solvent is evaporated and get the remainder, which is then purified by LC-MS. The fractions containing the target compound, concentrate, and get the remainder, to which is added a saturated aqueous solution of sodium bicarbonate and extracted with ethyl acetate. The organic layer is dried over anhydrous sodium sulfate and concentrated under reduced pressure. The solid is suspended in diethyl ether, filtered off, washed with diethyl ether and dried in a stream of air, getting mentioned in the title compound (15 mg, 21%) as a colorless powder.

Range1H-NMR (DMSO-d6) δ (ppm): 3,37 (2H, c), 3,40 (4H, m), of 3.56 (4H, m), 6,63 (1H, DD, J=2,4, 5,6 Hz), 7,01 (1H, m), 7,19 (2H, m), 7,25 (1H, DD, J=2,4, and 11.6 Hz), 7,40 (1H, d, J=2.4 Hz), a 7.62 (2H, DD, J=5,2, 8,8 Hz), 8,03 (1H, m)to 8.14 (1H, d, J=5.6 Hz), 9,29 (1H, c), 10,11 (1H, c), 10,27 (1H, c).

Example 81

N-(2-Fluoro-4-{2-[(pyrrolidin-1-carbonyl)amino]pyridine-4-yloxy}phenyl)-N'-(4-forfinal)malonamide

To a solution of N-[4-(2-aminopyridine-4-yloxy)-2-forfinal]-N'-(4-forfinal)malonamide (30 mg) in tetrahydrofuran (2.4 ml) is added triethylamine (0,021 ml), then added dropwise to phenylcarbamate (0,0189 ml), cooling in a bath containing ice water, and stirred for 20 minutes, the Reaction mixture was concentrated under reduced pressure. To a suspension of the residue is N,N-dimethylformamide (1.2 ml) add pyrrolidine (0,0251 ml), cooling in a bath containing ice water, after which the temperature was increased to room temperature and stirred for 1 hour. The reaction mixture is distributed between ethyl acetate (50 ml) and 1 N. aqueous sodium hydroxide solution (30 ml). The organic layer was washed with saturated saline and dried over anhydrous sodium sulfate. The solvent is evaporated and get the remainder, which is purified column chromatography on silica gel (eluent: hexane:ethyl acetate = 1:2, ethyl acetate, then ethyl acetate:methanol = 10:1). The fractions containing the target compound, concentrate, and get the remainder, which is subjected to filtration through silica gel (FUJI Silysia NH). The filtrate is concentrated under reduced pressure, obtaining a residue which is suspended in a mixture of hexane (3 ml), diethyl ether (1 ml) and ethanol (1 drop). The solid is filtered off, dried in the air flow and get listed in the title compound (12.3 mg, 33,0%) in powder form is a pale red color.

Range1H-NMR (DMSO-d6) δ (ppm): is 1.81 (4H, m)to 3.33 (4H, m)to 3.58 (2H, c), is 6.61 (1H, DD, J=2,4, 5.8 Hz), 7,00 (1H, m), 7,17 (2H, m), 7,24 (1H, m)to 7.50 (1H, d, J=2.4 Hz), a 7.62 (2H, m), 8,03 (1H, m)to 8.12 (1H, d, J=5,8 Hz), 8,71 (1H, c), 10,10 (1H, c), of 10.25 (1H, c).

ESI-MS (m/z): 496 [M+H]+.

Example 82

N-(4-Forfinal)-N'-[2-fluoro-4-(2-{[4-(pyrrolidin-1-yl)piperidine-1-carbonyl]amino}pyridine-4-yloxy)phenyl]malonamic

To a solution of N-[4-(2-aminopyridine-4-ylox is)-2-forfinal]-N'-(4-forfinal)malonamide (20 mg) in tetrahydrofuran (1.6 ml) is added triethylamine (0,014 ml), then added dropwise phenylcarbamate (0,0126 ml), cooling in a bath containing ice water, and stirred for 30 minutes, the Reaction mixture was concentrated under reduced pressure, add N,N-dimethylformamide (0.8 ml) and 4-(1-pyrrolidinyl)piperidine (31 mg) and stirred at room temperature for 1 hour. The reaction mixture is distributed between ethyl acetate (50 ml) and 1 N. aqueous sodium hydroxide solution (30 ml). The organic layer was washed with saturated saline, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting residue is purified column chromatography on silica gel (FUJI Silysia NH, eluent: hexane:ethyl acetate = 1:2, ethyl acetate, then ethyl acetate:methanol = 20:1). The fractions containing the target compound, concentrate, and get a solid substance that is suspended in a mixture of hexane (3 ml) and diethyl ether (1 ml), filtered, and get mentioned in the title compound (5.0 mg, 17%) as a powder pale yellow color.

Range1H-NMR (DMSO-d6) δ (ppm): 1.26 in (2H, m)of 1.66 (4H, m)to 1.79 (2H, m), 2,12 (1H, m), 2,46 (4H, m), of 2.86 (2H, m)to 3.58 (2H, c), of 3.97 (2H, m), 6,60 (1H, DD, J=1,6, 6,0 Hz), 7,01 (1H, m), 7,17 (2H, m), 7,24 (1H, DD, J=2,4, and 11.6 Hz), 7,63 (2H, DD, J=5,2, 8,8 Hz), 8,03 (1H, m)to 8.12 (1H, d, J=6.0 Hz), of 9.02 (1H, c), 10,11 (1H, c), 10,27 (1H, c).

ESI-MS (m/z): 579 [M+H]+.

Example 83

N-(4-{2-[3-(3-Diethylaminopropyl)-3-methylurea]pyridine-4-yloxy}phenyl)-N'-(4-fluoro who enyl)malonamide

To a solution of N-[4-(2-aminopyridine-4-yloxy)-2-forfinal]-N'-(4-forfinal)malonamide (35 mg) in tetrahydrofuran (2.8 ml) is added triethylamine (0,025 ml), then added dropwise to phenylcarbamate (0,022 ml) with cooling in a bath containing ice water, and stirred for 30 minutes, the Reaction mixture was concentrated under reduced pressure. To a suspension of the residue in N,N-dimethylformamide (1.4 ml) is added N,N-diethyl-N'-methylpropan-1,3-diamine (54,3 mg), cooling in a bath containing ice water, and stirred at room temperature for 30 minutes, the Reaction mixture was distributed between ethyl acetate (50 ml) and 1 N. aqueous sodium hydroxide solution (30 ml). The organic layer was washed with saturated saline and dried over anhydrous sodium sulfate. The solvent is evaporated and get the remainder, which is purified column chromatography on silica gel (FUJI Silysia NH, eluent: hexane:ethyl acetate = 1:1, then ethyl acetate). The fractions containing the crude product, concentrate, and get the remainder, which is optionally purified by LC-MS. The fractions containing the target compound, concentrate, and get the remainder, to which is added a saturated aqueous solution of sodium bicarbonate, and extracted with ethyl acetate. The organic layer was washed with saturated brine, concentrated under reduced pressure and get the remainder, which is shat in vacuum, getting listed in the title compound (4,1 mg, 8.2 percent) in the form of a powder pale brown color.

Range1H-NMR (DMSO-d6) δ (ppm): 1,00 (6H, t, J=6.8 Hz), to 1.70 (2H, m), 2,35-2,70 (6H, m), and 2.83 (3H, c), 3,30 (2H, m)to 3.58 (2H, c), to 6.57 (1H, m), 7,00 (1H, m), 7,17 (2H, m), 7.23 percent (1H, DD, J=2,6, and 11.4 Hz), 7,39 (1H, d, J=2,4 Hz), 7,63 (2H, DD, J=5,2, 8,8 Hz), 8,03 (1H, m), 8,10 (1H, d, J=5.6 Hz), to 10.09 (1H, c), of 10.25 (1H, c).

ESI-MS (m/z): 569 [M+H]+.

Example 84

N-{4-[2-(3,3-Dimethylurea)pyridine-4-yloxy]-2-forfinal}-N'-(4-forfinal)malonamide

To a solution of N-[4-(2-aminopyridine-4-yloxy)-2-forfinal]-N'-(4-forfinal)malonamide (35 mg) in tetrahydrofuran (2.8 ml) is added triethylamine (0,0245 ml), then added dropwise to phenylcarbamate (0,0221 ml), cooling in a bath containing ice water, and stirred for 30 minutes, the Reaction mixture was concentrated under reduced pressure. To a suspension of the residue in N,N-dimethylformamide (1.4 ml) is added dimethylamine (0,175 ml, 2,0M solution in tetrahydrofuran) and stirred at room temperature for 5 hours. Then add the hydrochloride diethylamine (35,8 mg) and triethylamine (0.2 ml) followed by stirring at room temperature for 2 hours. The reaction mixture is distributed between ethyl acetate (50 ml) and 1 N. aqueous sodium hydroxide solution (30 ml). The organic layer was washed with 1 N. aqueous sodium hydroxide solution and saturated saline in that order, after which the su is at over anhydrous sodium sulfate. The solvent is evaporated, receiving the remainder, which is then filtered through silica gel (FUJI Silysia NH). The filtrate is concentrated under reduced pressure, obtaining a residue, which is purified column chromatography on silica gel (eluent: hexane:ethyl acetate = 1:2, ethyl acetate, then ethyl acetate:methanol = 20:1 to 10:1). The fractions containing the target compound, concentrate, and get a solid substance, which is then suspended in a mixture of ethanol (0.5 ml) - diethyl ether (2.5 ml), filtered off and dried in air stream, receiving specified in the header connection (12,4 mg, 30%) in the form of a powder pale brown color.

Range1H-NMR (DMSO-d6) δ (ppm): 2,89 (6H, c)to 3.58 (2H, c), is 6.61 (1H, m), 7,01 (1H, m), 7,17 (2H, m), 7,24 (1H, m), the 7.43 (1H, c), 7,63 (2H, m), 8,03 (1H, m), 8,13 (1H, d, J=5.6 Hz), of 8.92 (1H, c), 10,10 (1H, c), 10,26 (1H, c).

ESI-MS (m/z) (neg.): 468 [M-H]-.

Example 85

N-(4-Forfinal)-N'-[2-methyl-4-(2-{[(4-pyrrolidin-1-yl)piperidine-1-carbonyl]amino}pyridine-4-yloxy)phenyl]malonamic

To a solution of N-[4-(2-aminopyridine-4-yloxy)-2-were]-N'-(4-forfinal)malonamide (60 mg) in a mixture of tetrahydrofuran (6 ml) - N,N-dimethylformamide (0,090 ml), add triethylamine (0,042 ml), then add phenylcarbamate (0,0378 ml), cooling in a bath containing ice water, and stirred for 20 minutes, the Reaction mixture was concentrated under reduced pressure. To a suspension of the residue in N,N-dimethylformamide (2.4 ml) is added 4(1-pyrrolidinyl)piperidine (93 mg) and stirred at room temperature for 5 hours. The reaction mixture is distributed between ethyl acetate (50 ml) and 1 N. aqueous sodium hydroxide solution (30 ml). The organic layer was washed with saturated saline, dried over anhydrous sodium sulfate and filtered through silica gel (FUJI Silysia NH). The filtrate is concentrated under reduced pressure, obtaining a residue, which is then suspended in ethanol (0.5 ml) and a mixture of ethyl acetate (1 ml) - diethyl ether (5 ml). The solid is filtered off, washed with diethyl ether and dried in air stream, receiving specified in the header of the connection (of 62.4 mg, 71,4%) as a colorless powder.

Range1H-NMR (DMSO-d6) δ (ppm): 1,22-and 1.54 (2H, m)of 1.66 (4H, m), 1,74 of-1.83 (2H, m)to 2.13 (1H, m), and 2.26 (3H, c), 2,47 (4H, m), of 2.86 (2H, m), 3,52 (2H, c), of 3.97 (2H, m), 6,55 (1H, DD, J=2,4, 5,6 Hz), of 6.96 (1H, DD, J=2,4, and 8.4 Hz), 7,05 (1H, d, J=2.4 Hz), 7,17 (2H, DD, J=8,8, 8,8 Hz), 7,37 (1H, d, J=2.4 Hz), EUR 7.57 (1H, d, J=8,4 Hz), to 7.64 (2H, DD, J=5,2, 8,8 Hz), 8,10 (1H, d, J=5.6 Hz), 9,16 (1H, c), for 9.64 (1H, c), 10,27 (1H, c).

ESI-MS (m/z): 575 [M+H]+.

Example 86

N-{4-[2-(3,3-Dimethylurea)pyridine-4-yloxy]-2-were}-N'-(4-forfinal)malonamide

To a solution of N-[4-(2-aminopyridine-4-yloxy)-2-were]-N'-(4-forfinal)malonamide (60 mg) in a mixture of tetrahydrofuran (6 ml) - N,N-dimethylformamide (0,090 ml), add triethylamine (0,042 ml), then add phenylcarbamate (0,038 ml) with cooling in a bath containing ice water, and stirred for 20 minutes, the Reaction mixture was concentrated under reduced on the no. To a suspension of the residue in N,N-dimethylformamide (2.4 ml) is added hydrochloride diethylamine (61 mg) and triethylamine (0,106 ml) followed by stirring at room temperature for 7 hours and 20 minutes, the Reaction mixture was distributed between ethyl acetate (50 ml) and 1 N. aqueous sodium hydroxide solution (30 ml). The organic layer was washed with saturated saline and dried over anhydrous sodium sulfate. The solvent is evaporated and get the remainder, which is then suspended in a mixture of ethanol (0.5 ml) - diethyl ether (5 ml), filtered off, washed with diethyl ether and dried in air stream, receiving specified in the header of the connection (and 52.7 mg, 75%) as a colorless powder.

Range1H-NMR (DMSO-d6) δ (ppm): and 2.26 (3H, c), 2,89 (6H, c), 3,52 (2H, c), 6,56 (1H, d, J=5.6 Hz), 6,97 (1H, d, J=8,4 Hz), 7,05 (1H, c), 7,17 (2H, DD, J=8,4, and 8.4 Hz), 7,39 (1H, c), EUR 7.57 (1H, d, J=8,4 Hz), to 7.64 (2H, DD, J=5,2, 8,4 Hz), 8,10 (1H, d, J=5.6 Hz), 8,87 (1H, c), 9,65 (1H, c), 10,27 (1H, c).

ESI-MS (m/z): 466 [M+H]+.

Example 87

N-(4-Forfinal)-N'-(2-methyl-4-{2-[(pyrrolidin-1-carbonyl)amino]pyridine-4-yloxy}phenyl)malonamide

To a solution of pyrrolidin-1-carboxylic acid [4-(4-amino-3-methylphenoxy)pyridine-2-yl]amide (100 mg) in N,N-dimethylformamide (2.0 ml) is added N-(4-forfinal)malonic acid (189 mg), triethylamine (0.5 ml) and hexaflurophosphate (1H-1,2,3-benzotriazol-1 iloxi)[three(dimethylamino)]phosphonium (425 mg) at room temperature and then what remesiana at 50° C for 5 hours. The reaction mixture is distributed between ethyl acetate (60 ml) and water (60 ml). The organic layer was washed with saturated aqueous sodium bicarbonate and saturated saline in this order, then dried over anhydrous sodium sulfate. The solvent is evaporated and get the remainder, which is purified column chromatography on silica gel (eluent: ethyl acetate-ethyl acetate:methanol = 10:1). The fractions containing the target compound, concentrate, and get a solid substance that is suspended in ethyl acetate, filtered off, washed with diethyl ether and dried in a stream of air, getting mentioned in the title compound (70 mg, 45%) as a colorless powder.

Range1H-NMR (DMSO-d6) δ (ppm): is 1.81 (4H, m), and 2.26 (3H, c), the 3.35 (4H, m), 3,52 (2H, c), 6,55 (1H, DD, J=2.0 a, 6,0 Hz), 6,97 (1H, DD, J=2,8, 8,8 Hz), 7,05 (1H, d, J=2.0 Hz), 7,17 (2H, DD, J=9,0, 9.0 Hz), of 7.48 (1H, d, J=2,8 Hz), 7,58 (1H, d, J=8,8 Hz), to 7.64 (2H, DD, J=5,3, 9.0 Hz), of 8.09 (1H, d, J=6.0 Hz), 8,65 (1H, c), for 9.64 (1H, c), 10,26 (1H, c).

Example 88

N-(4-Forfinal)-N'-(2-methyl-4-{2-[(morpholine-4-carbonyl)amino]pyridine-4-yloxy}phenyl)malonamide

To a solution of morpholine-4-carboxylic acid [4-(4-amino-3-methylphenoxy)pyridine-2-yl]amide (100 mg) in N,N-dimethylformamide (2.0 ml) is added at room temperature N-(4-forfinal)malonic acid (180 mg), triethylamine (0.5 ml) and hexaflurophosphate (1H-1,2,3-benzotriazol-1 iloxi)[three(dimethylamino)]fo phone (404 mg), followed by stirring at 50° C for 5 hours. The reaction mixture is distributed between ethyl acetate (60 ml) and water (60 ml). The organic layer was washed with saturated aqueous sodium bicarbonate and saturated saline in this order, then dried over anhydrous sodium sulfate. The solvent is evaporated to precipitate crystals, which are then suspended in ethyl acetate and filtered. The filtrate is again concentrated, receiving the remnant that purify column chromatography on silica gel (eluent: ethyl acetate - ethyl acetate:methanol = 10:1). The fractions containing the target compound, concentrate, and get a solid substance that is suspended in diethyl ether, filtered off, washed with diethyl ether and dried in a stream of air, getting mentioned in the title compound (13 mg, 8.4%) of the powder pale yellow color.

Range1H-NMR (DMSO-d6) δ (ppm): and 2.26 (3H, c), 3,40 (4H, m), 3,52 (2H, c), 3,55 (4H, m), to 6.57 (1H, DD, J=2,4, 5,6 Hz), 6,97 (1H, DD, J=2,4, and 8.4 Hz), 7,05 (1H, d, J=2.4 Hz), 7,17 (2H, DD, J=8,8, 8,8 Hz), 7,39 (1H, d, J=2,4 Hz), EUR 7.57 (1H, d, J=8,4 Hz), 7,63 (2H, DD, J=5,2, 8,8 Hz), 8,11 (1H, d, J=5.6 Hz), 9,24 (1H, c), for 9.64 (1H, c), 10,26 (1H, c).

Example 89

N-(3-Fluoro-4-{2-[3-methyl-3-(1-methylpiperidin-4-yl)ureido]pyridine-4-yloxy}phenyl)-N'-(4-forfinal)malonamide

3-[4-(4-Amino-2-pertenece)pyridine-2-yl]-1-methyl-1-(1-methylpiperidin-4-yl)urea (30.0 mg) was dissolved in N,N-dimethylformamide (1 ml) under nitrogen atmosphere and patentablauf at room temperature N-(4-forfinal)malonic acid (31.7 mg), the triethylamine (0,022 ml) and hexaflurophosphate (1H-1,2,3-benzotriazol-1 iloxi)[three(dimethylamino)]phosphonium (71 mg), followed by stirring for 3 hours. The reaction mixture is distributed between ethyl acetate and saturated aqueous ammonium chloride. The organic layer was washed with saturated aqueous ammonium chloride, water and saturated saline in this order, then dried over anhydrous sodium sulfate. The solvent is evaporated and get the remainder, which is purified column chromatography on silica gel (FUJI Silysia NH, eluent: ethyl acetate:ethanol = 9:1). The fractions containing the target compound, concentrate, and get the remainder, which is suspended in diethylacetal (1 ml). The solid is filtered off, dried in a stream of air, which is specified in the header connection (15,0 mg, 33.8 percent) in the form of a solid white color.

Range1H-NMR (CDCl3) δ (ppm): 1.50 is by 1.68 (2H, t, J=7 Hz), total 1.74 (2H, m), a 1.96 (2H, t, J=11,6 Hz), of 2.23 (3H, c), of 2.86 (5H, m), 3,49 (2H, m), of 4.05 (1H, m), 6,63 (1H, DD, J=2.0 a, 6,0 Hz), 7,02 (2H, m), 7,11 (1H, m), 7,21 (1H, d, J=8,8 Hz), 7,24 and 7.36 (1H, m), of 7.48 to 7.62 (3H, m), 7,68 (1H, m), 8,08 (1H, d, J=6.0 Hz), 8,89 (1H, Sirs), 9,42 (1H, Sirs).

ESI-MS (m/z): 553 [M+H]+.

Example 90

N-(4-Forfinal)-N'-(4-{2-[3-methyl-3-(1-methylpiperidin-4-yl)ureido]pyridine-4-yloxy}phenyl)malonamide

3-[4-(4-Aminophenoxy)pyridine-2-yl]-1-methyl-1-(1-methylpiperidin-4-yl)urea (20 mg) dissolved in N,N-dimethy the formamide (1 ml) and then at room temperature add N-(4-forfinal)malonic acid (22,3 mg), the triethylamine (0,016 ml) and hexaflurophosphate (1H-1,2,3-benzotriazol-1 iloxi)[three(dimethylamino)]phosphonium (49,8 mg) followed by stirring for 30 minutes the Reaction mixture is distributed between ethyl acetate (30 ml) and saturated aqueous sodium hydrogen carbonate (10 ml). The organic layer was washed with saturated aqueous sodium hydrogen carbonate (10 ml), water (10 ml) and saturated saline (10 ml) in that order, then dried over anhydrous sodium sulfate. The solvent is evaporated and get the remainder, which is purified column chromatography on silica gel (FUJI Silysia NH, eluent: ethyl acetate - ethyl acetate:ethanol = 9:1). The fractions containing the target compound, concentrate, and get the remainder, which is suspended in a mixture of diethylacetal (2 ml) - hexane (2 ml). The solid is filtered off, dried in a stream of air, which is specified in the header connection (21,3 mg, 70.8 per cent) in the form of a solid white color.

Range1H-NMR (CDCl3) δ (ppm): 1.50 is by 1.68 (2H, m)of 1.75 (2H, m), 1,99 (2H, t, J=12 Hz in), 2.25 (3H, c), 2,87 (5H, m), of 3.48 (2H, c), 4.09 to (1H, m), to 6.58 (1H, DD, J=2.0 a, 6,0 Hz), 7,02 (2H, m), was 7.08 (2H, d, J=8,8 Hz), 7,20 (1H, Sirs), 7,53 (2H, m), 7,56-to 7.68 (3H, m), of 8.06 (1H, d, J=6.0 Hz), 8,87-9,12 (2H, m).

ESI-MS (m/z): 557 [M+Na]+.

Example 91

N-(2-Fluoro-4-{2-[3-methyl-3-(1-methylpiperidin-4-yl)ureido]pyridine-4-yloxy}phenyl)-N'-(4-forfinal)malonamide

To a solution of 3-[4-(4-amino-3-pertenece)pyridine-2-yl]1-methyl-1-(1-methylpiperidin-4-yl)urea (40.5 mg) in tetrahydrofuran (20 ml) (example of getting 124) is added N,N-dimethylformamide (2 ml) under nitrogen atmosphere, then the tetrahydrofuran evaporated under reduced pressure. To the concentrated thus the solution at room temperature add N-(4-forfinal)malonic acid (42,6 mg), triethylamine (0,030 ml) and hexaflurophosphate (1H-1,2,3-benzotriazol-1 iloxi)[three(dimethylamino)]phosphonium (95,5 mg), followed by stirring for 1 hour. The reaction mixture is distributed between ethyl acetate (30 ml) and saturated aqueous ammonium chloride (15 ml). The organic layer was washed with saturated aqueous ammonium chloride (15 ml), water (15 ml) and saturated brine (15 ml) in that order, then dried over anhydrous sodium sulfate. The solvent is evaporated and get the remainder, which is purified column chromatography on silica gel (FUJI Silysia NH, eluent: ethyl acetate - ethyl acetate:ethanol = 95:5). The fractions containing the target compound, concentrate, and get the remainder, which is suspended in diethyl ether (1 ml). The solid is filtered off, dried in a stream of air, which is specified in the header of the connection (of 29.1 mg, 48,8%) as a pale green and yellow solid.

Range1H-NMR (CDCl3) δ (ppm): 1,48-1,71 (2H, m), of 1.78 (2H, m)2,07 (2H, m)to 2.29 (3H, c), 2,80-3,00 (5H, m), 3,55 (2H, m)to 4.16 (1H, m), 6,55 (1H, DD, J=2,4, 6,0 Hz), 6,92 (2H, d, J=8,8 Hz), 7,05 (2H, m), 7,21 (1H, Sirs), 7,53 (2H, m), of 7.69 (1H, d, J=2.4 Hz), 8,08 (1H, d, J=6.0 Hz), compared to 8.26 (1H, m), 8,63 (1H, Sirs), 8,80 (1H, Shir.is).

ESI-MS (m/z): 553 [M+H]+.

Example 92

N-(2-Fluoro-4-{2-[(4-methyl-[1,4]diazepan-1-carbonyl)amino]pyridine-4-yloxy}phenyl)-N'-(4-forfinal)malonamide

To a solution of N-[4-(2-aminopyridine-4-yloxy)-2-forfinal]-N'-(4-forfinal)malonamide (17.6 mg) in tetrahydrofuran (2.0 ml) is added triethylamine (0,0154 ml), then added dropwise to phenylcarbamate (0,00833 ml), cooling in a bath containing ice water, and stirred for 10 minutes, the Reaction mixture was concentrated under reduced pressure. To the obtained residue is added N,N-dimethylformamide (1.0 ml) and 1-methylhomopiperazine (0,0193 ml) followed by stirring at room temperature for 8 hours. The reaction mixture is distributed between ethyl acetate (50 ml) and water (30 ml). The organic layer was washed with saturated saline (30 ml×3) and dried over anhydrous sodium sulfate. The solvent is evaporated and get a solid substance, which is then suspended in a mixture of hexane:diethyl ether = 1:1 (3.0 ml), filtered off and dried in air stream, receiving specified in the header connection (10,2 mg, 42.8 per cent) in the form of a powder pale yellow color.

Range1H-NMR (DMSO-d6) δ (ppm): 1,25 (2H, m), of 1.78 (2H, m), 2,24 (3H, c), a 2.45 (2H, m), 3,51 (4H, m)to 3.58 (2H, m), is 6.61 (1H, DD, J=2,4, 5,6 Hz), 7,02 (1H, m), 7,17 (2H, DD, J=9,0, 9.0 Hz), 7,25 (1H, DD, J=2,4, 8.0 Hz), of 7.48 (1H, d, J=2.4 Hz), 7,63 (2H, DD, J=5.0 and 9.0 Hz), of 8.04 (1H, m), 8,13 (1H, d, J=5.6 Hz), 8,82 (1H, c), 10,10 (1H, c), 10,26 (1H, c).

ESI-M is (m/z): 539 [M+H] +.

Example 93

N-[2-Fluoro-4-(2-{3-methyl-3-[3-(4-methylpiperazin-1-yl)propyl]ureido}pyridine-4-yloxy)phenyl]-N'-(4-forfinal)malonamide

To a solution of N-[4-(2-aminopyridine-4-yloxy)-2-forfinal]-N'-(4-forfinal)malonamide (17.6 mg) in tetrahydrofuran (2.0 ml) is added triethylamine (0,0154 ml), then added dropwise to phenylcarbamate (0,00833 ml), cooling in a bath with ice, and stirred for 10 minutes, the Reaction mixture was concentrated under reduced pressure. To the obtained residue is added N,N-dimethylformamide (1.0 ml) and methyl-[3-(4-methylpiperazin-1-yl)propyl]amine (67,1 mg), followed by stirring at room temperature for 3 hours. Then add methyl-[3-(4-methylpiperazin-1-yl)propyl]amine (34,5 mg) and stirred at room temperature for 3 hours. Add another portion of methyl-[3-(4-methylpiperazin-1-yl)propyl]amine (34,5 mg) and stirred at room temperature for 2.5 hours. The reaction mixture is distributed between ethyl acetate (50 ml) and water (30 ml). The organic layer was washed with saturated saline (30 ml×3) and dried over anhydrous sodium sulfate. The solvent is evaporated and get the remainder, which is purified column chromatography on silica gel (FUJI Silysia NH, eluent: ethyl acetate:methanol = 20:1-10:1). The fractions containing the target compound, concentrate, and get the remainder, which is suspended in a mixture atilas the Tata (0.5 ml) and hexane (2.5 ml). After deposition of solids in the supernatant removed. The remaining solvent evaporated under reduced pressure and get the remainder, which is dried in vacuum, obtaining specified in the header connection (to 46.7 mg, 12,4%) as a colorless powder.

Range1H-NMR (DMSO-d6) δ (ppm): 1,68 (2H, m), 2,11-2,60 (11H, m), of 2.81 (3H, c), and 3.31 (4H, m)to 3.58 (2H, c), 6,59 (1H, DD, J=2,0, 5.6 Hz), 7,01 (1H, m), 7,17 (2H, DD, J=8,8, 8,8 Hz), 7,24 (1H, DD, J=2,8, 7,6 Hz), 7,42 (1H, d, J=2.0 Hz), 7,63 (2H, DD, J=4,8, 8,8 Hz), 8,03 (1H, d, J=5.6 Hz), 8,10 (1H, d, J=5.6 Hz), for 9.47 (1H, Sirs), 10,10 (1H, c), 10,26 (1H, c).

Range H-NMR (CDCl3) δ (ppm): 1,78 (2H, m), 2.26 and-2,78 (11H, m), 2,89 (3H, c), to 3.38 (4H, m), 3,55 (2H, c), of 6.52 (1H, DD, J=2,2, 5.6 Hz), to 6.88 (2H, m), 7,01 (2H, m), 7,51-EUR 7.57 (3H, m), of 8.06 (1H, d, J=5.6 Hz), to 8.20 (1H, m,), 9,07 (1H, c), 9,13 (1H, c).

Compounds of the following examples are synthesized by methods described in the examples 1-93.

Example 94

Pyrrolidin-1-thiocarbonic acid {4-[3-chloro-4-(3-phenylacetylamino)phenoxy]pyridine-2-yl}amide

Specified in the title compound (15.7 mg, 14.5 percent) receive in the form of a solid pale yellow color of the 2-phenylacetylide (0,067 ml), potassium thiocyanate (99,1 mg) and 4-(4-amino-2-pertenece)-2-[(pyrrolidin-1-yl)thiocarbanilide]pyridine (99,6 mg).

Range1H-NMR (CDCl3) δ (ppm): 2,05 (4H, m), 3,40-4,10 (6H, m), 6,62 (1H, m), to 7.09 (1H, DD, J=2,8, 9,2 Hz), 7,20 is 7.50 (6H, m), 7,72 (1H, m), 8,11 (1H, m), at 8.36 (2H, DD, J=9,2 Hz), 8,55 (1H, m), 12,42 (1H, c).

Example 95

4-{3-Chloro-4-[3-(2-phenylacetyl)touraid]phenoxy}-2-[(Pyrrhus is lidin-1-yl)carbylamine]pyridine

Specified in the header connection (88,8 mg, 35%) are obtained in the form of white crystals of 2-phenylacetylide (0.2 ml), potassium thiocyanate (292 mg) and 4-(4-amino-3-chlorophenoxy)-2-[(pyrrolidin-1-yl)carbylamine]pyridine (166 mg).

Range1H-NMR (DMSO-d6) δ (ppm): 1,70-1,90 (4H, m), 3,20-3,40 (4H, m), 3,82 (2H, c), 6,59 (1H, DD, J=2,4, 5,6 Hz), 7,18 (1H, m), 7,20-7,40 (5H, m), the 7.43 (1H, d, J=3.2 Hz), 7,53 (1H, d, J=2.0 Hz), of 8.04 (1H, d, J=8,8 Hz), 8,13 (1H, d, J=5.6 Hz), a total of 8.74 (1H, c), 11,88 (1H, c), 12,36 (1H, c).

Example 96

4-{3-Chloro-4-[3-(2-phenylacetyl)touraid]phenoxy}-2-[(morpholine-4-yl)carbylamine]pyridine

Specified in the header connection (to 34.3 mg, 41%) are obtained in the form of a white powder of 2-phenylacetylide (125 mg), potassium thiocyanate (157 mg) and 4-(4-amino-3-chlorophenoxy)-2-[(morpholine-4-yl)carbylamine]pyridine (56,2 mg).

Range1H-NMR (DMSO-d6) δ (ppm): 3,30 is 3.40 (4H, m), 3,50-3,60 (4H, m), a-3.84 (2H, c), 6,62 (1H, DD, J=2,4, 5,6 Hz), 7,20 is 7.50 (8H, m), of 8.06 (1H, d, J=8,8 Hz), 8,16 (1H, d, J=5.6 Hz), was 9.33 (1H, c), 11,90 (1H, c), 12,38 (1H, c).

Example 97

4-{4-[3-(2-Cyclopropylethyl)touraid]-2-fervency}-2-[(pyrrolidin-1-yl)carbylamine]pyridine

Specified in the header connection (61,9 mg, 42%) are obtained in the form of crystals of pale yellow 2-cyclopropylacetic acid (114,2 mg), oxalicacid (0,105 ml), potassium thiocyanate (222 mg) and 4-(4-amino-2-pertenece)-2-[(pyrrolidin-1-yl)carbylamine]pyridine (103 mg).

Range1H-NMR (DMSO-d6) δ (ppm): 0,15-0,25 (2H, m), 0,40-,60 (2H, m)of 1.02 (1H, m), 1,80-1,90 (4H, m), of 2.38 (2H, d, J=7,2 Hz), 3,20-3,40 (4H, m), is 6.61 (1H, DD, J=2,4, 6,0 Hz), 7,30-of 7.60 (3H, m), 8,03 (1H, m), 8,13 (1H, d, J=6.0 Hz), a total of 8.74 (1H, c), 11,51 (1H, c), 12,66 (1H, c).

Example 98

4-{4-[-3-(3-ethoxypropionate)touraid]phenoxy}-2-[(pyrrolidin-1-yl)carbylamine]pyridine

Specified in the header connection (10,2 mg, 13%) are obtained in the form of a powder pale yellow color of the 3-ethoxypropionate acid (50 mg), thionyl chloride (0.5 ml), potassium thiocyanate (81 mg) and 4-(4-aminophenoxy)-2-[(pyrrolidin-1-yl)carbylamine]pyridine (50 mg).

Range1H-NMR (DMSO-d6) δ (ppm): a 1.11 (3H, t, J=7.2 Hz), 1,70-1,90 (4H, m), 2.70 height is 2.75 (2H, m), 3,20-3,70 (8H, m), 6,60 (1H, DD, J=2,4, 5,6 Hz), 7.18 in-7,21 (2H, m), 7,52 (1H, c), 7,72 to 7.75 (2H, m), 8,13 (1H, d, J=5.6 Hz), 8,72 (1H, c), 11,50 (1H, c), 12,51 (1H, c).

Example 99

Piperidine-1-carboxylic acid {4-[3-chloro-4-(3-phenylacetylamino)phenoxy]pyridine-2-yl}amide

Specified in the title compound (20 mg, of 0.038 mmol, 25%) was obtained as colorless powder from piperidine-1-carboxylic acid [4-(4-amino-3-chlorophenoxy)pyridine-2-yl]amide (52 mg, 0.15 mmol) and 0,1M solution phenylacetonitrile in acetonitrile (7.5 ml, 0.75 mmol).

Range1H-NMR (DMSO-d6) δ (ppm): 1,45 (4H, m), and 1.54 (2H, m), 3,39 (4H, m), a-3.84 (2H, c), 6,59 (1H, DD, J=2,4, 5,6 Hz), 7,19 (1H, DD, J=2,6, 8,8 Hz), 7,29 (1H, m), 7,33-7,38 (4H, m), 7,45 (2H, m), of 8.06 (1H, d, J=8,8 Hz), of 8.15 (1H, d, J=5.6 Hz), 9,19 (1H, c), 11,90 (1H, c), 12,38 (1H, c).

ESI-MS (m/z): 524 [M+H]+.

Example 100

Azetidin-1-carboxylic acid {4-[3-chloro-4-(3-phenylacetylamino is eido)phenoxy]pyridine-2-yl}amide

Specified in the title compound (27 mg, 0,054 mmol, 36%) was obtained as colorless powder from azetidin-1-carboxylic acid [4-(4-amino-3-chlorophenoxy)pyridine-2-yl]amide (48 mg, 0.15 mmol) and 0,1M solution phenylacetonitrile in acetonitrile (7.5 ml, 0.75 mmol).

Range1H-NMR (DMSO-d6) δ (ppm): to 2.13 (2H, m), a-3.84 (2H, c), of 3.95 (4H, m), 6,60 (1H, DD, J=2.0 a, 6,0 Hz), 7,19 (1H, DD, J=2,8, and 8.4 Hz), 7,27 (1H, m), 7,35 (4H, m), 7,45 (1H, d, J=2,8 Hz), 7,56 (1H, d, J=2.0 Hz), 8,07 (1H, d, J=8,4 Hz)to 8.14 (1H, d, J=6.0 Hz), 9,13 (1H, c), 11,90 (1H, c), 12,38 (1H, c).

Example 101

1-(3-Diethylaminopropyl)-3-[4-(2-fluoro-4-{3-[(4-forfinal)acetyl]touraid}phenoxy)pyridine-2-yl]urea

Specified in the title compound (0.8 mg, 0.6 per cent) obtained as colorless powder from 1-[4-(2-aminopyridine-4-yloxy)-3-forfinal]-3-[(4-forfinal)acetyl]thiourea (100 mg), phenylcarbamate (0,0454 ml) and N,N-diethyl-1,3-propandiamine (0,151 ml).

Range1H-NMR (CDCl3) δ (ppm): 1.26 in (6H, t, J=7.2 Hz), to 1.98 (2H, m), of 3.07 (6H, m), and 3.31 (2H, m), 3,68 (2H, c), only 6.64 (1H, DD, J=2.0 a, and 6.6 Hz), 7,05 (2H, DD, J=8,4, and 8.4 Hz), to 7.15 (1H, DD, J=8,8, 8,8 Hz), 7,19-of 7.25 (3H, m), to 7.35 (1H, m), 7,86 (1H, d, J=6.6 Hz), 7,94 (1H, DD, J=2,2, and 11.4 Hz), to 8.41 (1H, Sirs), a total of 8.74 (1H, c), 12,04 (1H, Sirs), 12,46 (1H, c).

ESI-MS (m/z): 571 [M+H]+.

Example 102

1 Methylpiperidin-4-carboxylic acid (4-{2-fluoro-4-[3-(4-forfinal)acetylthiourea]phenoxy}pyridine-2-yl)amide

Ispolzuete-butyl 4-(4-{2-fluoro-4-[3-(4-forfinal)acetylthiourea]phenoxy}pyridine-2-ylcarbonyl)piperidine-1-carboxylate (8,8 mg, 0,062 mmol) and triperoxonane acid (0,50 ml), get the crude piperidine-4-carboxylic acid (4-{2-fluoro-4-[3-(4-forfinal)acetylthiourea]phenoxy}pyridine-2-yl}amide (ESI-MS (m/z): 526). Using the crude product, formalin (37% aqueous solution; 0,0231 ml), acetic acid (0,0142 ml) and triacetoxyborohydride sodium (26,3 mg), get mentioned in the title compound (1.1 mg, 3,29%) as a colorless powder.

Range1H-NMR (DMSO-d6) δ (ppm): 1,70 of-1.83 (2H, m)to 1.99 (2H, m)to 2.67 (1H, m), was 2.76 (3H, m), 2,84 are 2.98 (2H, m), of 3.45 (2H, m), 3,83 (2H, c), 6,74 (1H, DD, J=2,4, 6,0 Hz), 7,18 (2H, m), of 7.36-7,42 (3H, m), 7,53 (1H, m), to 7.67 (1H, d, J=2.4 Hz), 8,00 (1H, DD, J=2,2, and 12.2 Hz), 8,23 (1H, d, J=6.0 Hz), of 10.76 (1H, c), 11,81 (1H, c), 12,47 (1H, c).

ESI-MS (m/z): 540 [M+H]+.

Example 103

Morpholine-4-carboxylic acid {4-[3-methyl-4-(3-phenylacetylamino)phenoxy]pyridine-2-yl}amide

Specified in the title compound (7.0 mg, 6.9 per cent) receive in the form of a solid pale brown color of the 2-phenylacetylide (0,038 ml), potassium thiocyanate (58 mg) and morpholine-4-carboxylic acid [4-(4-amino-3-methylphenoxy)pyridine-2-yl]amide (66 mg).

Range1H-NMR (DMSO-d6) δ (ppm): 2,19 (3H, c), is 3.41 (4H, m), of 3.56 (4H, m), 3,83 (2H, c), to 6.57 (1H, m), 7,01 (1H, d, J=8,4 Hz), 7,10 (1H, c), 7,30 (1H, m), 7,35 (4H, m), 7,44 (1H, m), the 7.65 (1H, m), 8,14 (1H, m), 9,27 (1H, m), 11,74 (1H, c), 12,04 (1H, c).

ESI-MS (m/z)(neg.): 504 [M-H]-.

Example 104

Pyrrolidin-1-carboxylic acid {4-[3-methyl-4-(3-phenylacetylamino)phenoxy]pyridine-2-yl}amide

Specified in the title compound (18 mg, 18%) was obtained as colorless powder from 2-phenylacetylide (0,038 ml), potassium thiocyanate (58 mg) and pyrrolidine-1-carboxylic acid 4-(4-amino-3-methylphenoxy)pyridine-2-yl]amide (62 mg).

Range1H-NMR (DMSO-d6) δ (ppm): is 1.81 (4H, m), 2,19 (3H, c), the 3.35 (4H, m), 3,83 (2H, c), 6,55 (1H, m), 7,01 (1H, m), 7,10 (1H, c), 7,28 and 7.36 (5H, m), 7,53 (1H, c), 7,66 (1H, m)to 8.12 (1H, d, J=6.0 Hz), to 8.70 (1H, Sirs), 11,73 (1H, c), 12,04 (1H, c).

Example 105

4-{3-Chloro-4-[3-(2-phenylacetyl)touraid]phenoxy}-2-(cyclopropanecarbonyl)pyridine

Using 2-amino-4-(4-amino-3-chlorophenoxy)pyridine (471 mg), triethylamine (0,384 ml), cyclopropanecarbonyl acid (0,22 ml) and hexaflurophosphate (1H-1,2,3-benzotriazol-1 iloxi)[three(dimethylamino)]phosphonium (1216 mg)obtain crude 4-(4-amino-3-chlorophenoxy)-2-(cyclopropanecarbonyl)pyridine (63 mg). Using a crude product (63 mg), 2-phenylacetylene (97 mg) and potassium thiocyanate (122 mg), get mentioned in the title compound (30,6 mg, output from the two processes of 6.4%) as white crystals.

Range1H-NMR (DMSO-d6) δ (ppm): 0,87 (2H, m), 1,25 (2H, m), 1,99 (1H, m), 3,85 (2H, c), of 6.71 (1H, m), 7,21 (1H, m), 7,22-7,40 (5H, m), of 7.48 (1H, d, J=3.2 Hz), 7,72 (1H, d, J=2.0 Hz), 8,08 (1H, d, J=8,8 Hz), 8,23 (1H, d, J=5.6 Hz), 10,91 (1H, c), 11,91 (1H, c), 12,40 (1H, c).

Example 106

4-{2-Fluoro-4-[3-(2-cyclopropylethyl)ureido]phenoxy}-2-[(pyrrolidin-1-yl)carbylamine]pyridine

Specified in the header connection (8,5 the g 7,7%) are obtained in the form of white crystals of 2-cyclopropylacetic (124 mg), oxalicacid (0,109 ml) and 4-(4-amino-2-pertenece)-2-[(pyrrolidin-1-yl)carbylamine]pyridine (79 mg).

Range1H-NMR (DMSO-d6) δ (ppm): to 0.17 to 0.21 (2H, m), 0,47-0,52 (2H, m)of 1.03 (1H, m), 1,70-1,90 (4H, m)to 2.29 (2H, d, J=7,2 Hz), 3,20-3,40 (4H, m), 6,60 (1H, DD, J=2,4, 5,6 Hz), 7,30-of 7.48 (3H, m), 7,79 (1H, DD, J=2,4, 8,8 Hz), 8,11 (1H, d, J=5.6 Hz), to 8.70 (1H, c), 10,70-a 10.74 (2H, m).

Example 107

4-(2-Fluoro-4-{3-[2-(4-forfinal)acetyl]ureido}phenoxy)-2-[(methylamino)carbylamine]pyridine

Specified in the title compound (9.8 mg, 5.6 per cent) receive in the form of a powder pale yellow color of the 2-(4-forfinal)ndimethylacetamide (153,2 mg), oxalicacid (0,110 ml) and 4-(4-amino-2-pertenece)-2-[(methylamino)carbylamine]pyridine (107 mg).

Range1H-NMR (DMSO-d6) δ (ppm): to 2.67 (3H, d, J=4.4 Hz in), 3.75 (2H, c), 6,55 (1H, DD, J=2,4, 5,6 Hz)6,91 (1H, c), 7,15-7,41 (6H, m), to 7.77 (1H, DD, J=2,4, 8,8 Hz), 7,82 (1H, m), of 8.06 (1H, d, J=5.6 Hz), to 9.15 (1H, c), of 10.58 (1H, c), 11,03 (1H, c).

Example 108

1-(3-Diethylaminopropyl)-3-{4-[2-fluoro-4-(3-phenylacetylamino)phenoxy]pyridine-2-yl}urea

Specified in the header connection (27,1 mg, 19%) was obtained as colorless powder from 1-(3-diethylaminopropyl)-3-[4-(4-amino-2-pertenece)pyridine-2-yl]urea (100 mg, 0,266 mmol) and 0,5M solution fenilizotsianata in hexane (3.4 ml, the sample receiving 1).

Range1H-NMR (DMSO-d6) δ (ppm): 0,93 (6H, t, J=7,0 Hz)of 1.53 (2H, m), 2,35 is 2.46 (6H, m), of 3.13 (2H, m), 3,74 (2H, c), 6,55 (1, d, J=5.6 Hz), make 6.90 (1H, c), 7,27-7,41 (7H, m), 7,78 (1H, d, J=8,8 Hz), 8,01 (1H, m), with 8.05 (1H, d, J=5.6 Hz), 9,11 (1H, c), 10,61 (1H, c)11,05 (1H, c).

ESI-MS (m/z): 537 [M+H]+.

Example 109

1 Methylpiperidin-4-carboxylic acid {4-[2-fluoro-4-(3-phenylacetylamino)phenoxy]pyridine-2-yl}amide

Using tert-butyl 4-{4-[2-fluoro-4-(3-phenylacetylamino)phenoxy]pyridine-2-ylcarbonyl}piperidine-1-carboxylate (60 mg, 0,101 mmol) and triperoxonane acid (0,50 ml), get the crude piperidine-4-carboxylic acid {4-[2-fluoro-4-(3-phenylacetylamino)phenoxy]pyridine-2-yl}amide (ESI-MS (m/z): 492). Using the crude product, formalin (37% aqueous solution; 0,0376 ml, worn : 0.505 mmol), acetic acid (0,0231 ml, 0,404 mmol) and triacetoxyborohydride sodium (42,8 mg, 0,202 mmol)are specified in the header of the connection (of 51.1 mg, 22,5%) as a colorless powder.

Range1H-NMR (DMSO-d6) δ (ppm): 1,49-to 1.61 (2H, m)to 1.67 (2H, m), of 1.80 (2H, m)to 2.13 (3H, c), 2,39 (1H, m), was 2.76 (2H, m), 3,74 (2H, c), of 6.71 (1H, m), 7,25-7,42 (7H, m), of 7.64 (1H, d, J=1.6 Hz), 7,78 (1H, m), 8,19 (1H, d, J=6.0 Hz), 10,51 (1H, c), to 10.62 (1H, c)11,05 (1H, c).

ESI-MS (m/z): 506 [M+H]+.

Example 110

Pyrrolidin-1-carboxylic acid {4-[3-methyl-4-(3-phenylacetylamino)phenoxy]pyridine-2-yl}amide

Specified in the title compound (6.8 mg, and 4.5%) obtained as colorless powder from pyrrolidin-1-carboxylic acid [4-(4-amino-3-methylphenoxy)pyridine-2-yl]amide (100 mg, 0.32 mmol) and fenilizotsianata (2.0 ml, 1.0 mmol, 0,5M solution in hexane, n is the iMER obtain 1).

Range1H-NMR (DMSO-d6) δ (ppm): 1,80 (4H, m), 2,22 (3H, c)to 3.34 (4H, m in), 3.75 (2H, c), is 6.54 (1H, DD, J=2,4, 5,6 Hz), of 6.99 (1H, DD, J=2,4, and 8.4 Hz), 7,07 (1H, d, J=2.4 Hz), 7,27-7,37 (5H, m), 7,46 (1H, d, J=2.4 Hz), 8,01 (1H, d, J=8,4 Hz), 8,08 (1H, d, J=5.6 Hz), 8,64 (1H, c), 10,48 (1H, c), 11,04 (1H, c).

ESI-MS (m/z): 474 [M+H]+.

Example 111

Morpholine-4-carboxylic acid {4-[2-methyl-4-(3-phenylacetylamino)phenoxy]pyridine-2-yl}amide

Specified in the title compound (10.5 mg, 8,8%) obtained as colorless powder from morpholine-4-carboxylic acid [4-(4-amino-2-methylphenoxy)pyridine-2-yl]amide (80 mg, 0.24 mmol) and fenilizotsianata (0,5M solution in hexane; 2.0 ml).

Range1H-NMR (DMSO-d6) δ (ppm): 2,07 (3H, c), 3,39 (4H, m), 3,55 (4H, m), of 3.73 (2H, c), 6,51 (1H, DD, J=2,4, 5,6 Hz),? 7.04 baby mortality (1H, d, J=8,8 Hz), 7,26-to 7.35 (6H, m), 7,46 (1H, d, J=9,2 Hz), 7,50 (1H, c), of 8.09 (1H, d, J=5,6 Hz), of 9.21 (1H, c), 10,49 (1H, c), 10,97 (1H, c).

ESI-MS (m/z): 512 [M+Na]+.

Example 112

Pyrrolidin-1-carboxylic acid {4-[2-methyl-4-(3-phenylacetylamino)phenoxy]pyridine-2-yl}amide

Specified in the title compound (11.3 mg, to 9.32%) was obtained as colorless powder from pyrrolidin-1-carboxylic acid [4-(4-amino-2-methylphenoxy)pyridine-2-yl]amide (80 mg, 0,256 mmol) and fenilizotsianata (0,5M solution in hexane; 2.0 ml).

Range1H-NMR (DMSO-d6) δ (ppm): 1,80 (4H, m)2,07 (3H, c), of 3.32 (4H, m), 3,74 (2H, c), of 6.49 (1H, d, J=6.0 Hz),? 7.04 baby mortality (1H, d, J=9.0 Hz), 7.23 percent-7,38 (6H, m), 7,45 (1H, d, J=9.0 Hz), 7,50 (1H, c), 8,07 (1H, d, J=6.0 Hz), to 8.62 (1H, c), 10,49 (1H, c), 10,96 (1H, c).

ESI-MS m/z: 496 [M+Na] +.

Example 113

N-(4-Terbisil)-N'-(3-fluoro-4-{2-[(pyrrolidin-1-yl)carbylamine]pyridine-4-yloxy}phenyl)oxalate

Specified in the header of the connection (of $ 74.4 mg, 48%) are obtained as white crystals from 4-(4-amino-2-pertenece)-2-[(pyrrolidin-1-yl)carbylamine]pyridine (100 mg), triethylamine (0,132 ml), N-(4-terbisil)oxalic acid (187 mg) and hexaflurophosphate (1H-1,2,3-benzotriazol-1 iloxi)[three(dimethylamino)]phosphonium (419 mg).

Range1H-NMR (DMSO-d6) δ (ppm): 1,70-1,90 (4H, m), 3,20-3,40 (4H, m), to 4.38 (2H, d, J=6.0 Hz), is 6.61 (1H, DD, J=2,4, 5,6 Hz), 7,16 (2H, m), 7,34-7,40 (3H, m), 7,46 (1H, d, J=2.0 Hz), 7,78 (1H, d, J=8,8 Hz), of 7.97 (1H, m), 8,11 (1H, d, J=5.6 Hz), to 8.70 (1H, c), 9,63 (1H, t, J=6.0 Hz), 11,03 (1H, c).

Example 114

N-(4-Forfinal)-N'-{4-[2-(2,2-dimethylpropanolamine)pyridine-4-yloxy]-2-forfinal}malonamic

Specified in the title compound (3.7 mg, 15%) are obtained in the form of a powder pale yellow color of N-(4-forfinal)-N'-[4-(2-aminopyridine-4-yloxy)-2-forfinal}malonamide (20.0 mg), triethylamine (0,020 ml) and pivaloate (0,009 ml).

Range1H-NMR (CDCl3) δ (ppm): of 1.29 (9H, c), of 3.57 (2H, c), 6,63 (1H, m), 6.90 to-6,93 (2H, m), 7,02-7,07 (2H, m), 7,51-of 7.55 (2H, m), a 7.85 (1H, d, J=2.4 Hz), 8,03 (1H, c), 8,13 (1H, d, J=5.6 Hz), of 8.28 (1H, m), 8,69 (1H, Sirs), of 8.90 (1H, Sirs).

Example 115

N-(4-Forfinal)-N'-(4-{2-[(2-dimethylamino)acetylamino]pyridine-4-yloxy}-2-forfinal)malonamide

Specified in the title compound (8.6 mg, 14%) are obtained in the form of a white powder of N-(4-forfinal-N'-[4-(2-aminopyridine-4-yloxy)-2-forfinal]malonamide (50 mg), triethylamine (0,088 ml), N,N-dimethylglycine (65 mg) and hexaflurophosphate (1H-1,2,3-benzotriazol-1 iloxi)[three(dimethylamino)]phosphonium (278 mg).

Range1H-NMR (CDCl3) δ (ppm): is 2.37 (6H, c)a 3.06 (2H, c), 3,55 (2H, c), 6,63 (1H, DD, J=2,4, 5,6 Hz), 6,93 (2H, d, J=8,8 Hz), 7,05 (2H, m), 7,30-of 7.55 (2H, m), 7,87 (1H, m), 8,17 (1H, d, J=5.6 Hz), 8,29 (1H, m), to 8.57 (1H, Sirs), 8,79 (1H, Sirs), RS 9.69 (1H, Sirs).

Example 116

(4-{3-Fluoro-4-[2-(4-tortenelmebol)acetylamino]phenoxy}pyridine-2-yl)carbamino acid methyl ester

Specified in the title compound (5.0 mg, 39%) are obtained in the form of a white powder of N-(4-forfinal)-N'-[4-(2-aminopyridine-4-yloxy)-2-forfinal]malonamide (11.3 mg), triethylamine (0,016 ml) and methylchloroform (0,0044 ml).

Range1H-NMR (DMSO-d6) δ (ppm): 3,59 (2H, c), 3,63 (3H, c), of 6.68 (1H, m), 7,00-7,30 (4H, m), 7,41 (1H, c), 7,50-of 7.70 (2H, m), with 8.05 (1H, m), 8,16 (1H, m), 10,11 (1H, c), 10,26 (1H, c), 10,29 (1H, c).

Example 117

N-(4-{2-[3-(3-Diethylaminopropyl)-3-methylurea]pyridine-4-yloxy}-3-forfinal}-N'-(4-forfinal)malonamide

Specified in the title compound (31 mg, 42%) are obtained in the form of a powder pale yellow color of 1-(3-diethylaminopropyl)-3-[4-(4-amino-2-pertenece)pyridine-2-yl]-1-metalmachine (50 mg), N-(4-forfinal)malonic acid (76,3 mg), triethylamine (0,0539 ml) and hexaflurophosphate (1H-1,2,3-benzotriazol-1 iloxi)[three(dimethylamino)]phosphonium (171 mg).

Range1H-NMR (DMSO-d6) δ (ppm): 0,97 (6H, t, J=7.0 Hz), 1,68 (2H, m), 2,31-2,60 (6H, m), and 2.79 (3H, c), or 3.28 (2H, is), to 3.49 (2H, c), 6,55 (1H, DD, J=2,4, 6,0 Hz), 7,17 (2H, DD, J=9,2, 9,2 Hz), 7,30-7,41 (3H, m), 7,63 (2H, DD, J=5,2, 9,2 Hz), 7,82 (1H, DD, J=2,4, 8,8 Hz), 8,07 (1H, d, J=6.0 Hz), of 10.21 (1H, Sirs), 10,26 (1H, c), 10,50 (1H, c).

Example 118

N-(4-{2-[3-(3-Diethylaminopropyl)ureido]pyridine-4-yloxy}-3-forfinal}-N'-(4-forfinal)malonamide

Specified in the title compound (31 mg, 42%) are obtained in the form of a powder pale yellow color of 1-(3-diethylaminopropyl)-3-[4-(4-amino-2-pertenece)pyridine-2-yl]urea (50 mg), N-(4-forfinal)malonic acid (78,7 mg), triethylamine (0.2 ml) and hexaflurophosphate (1H-1,2,3-benzotriazol-1 iloxi)[three(dimethylamino)]phosphonium (176 mg).

Range1H-NMR (DMSO-d6) δ (ppm): 0,93 (6H, t, J=6.8 Hz), 1,53 (2H, m), is 2.37 (2H, m), 2,43 (4H, q, J=6.8 Hz), of 3.13 (2H, m), 3,49 (2H, c), 6,56 (1H, DD, J=2,4, 5.8 Hz), 6.89 in (1H, d, J=2.4 Hz), 7,17 (2H, DD, J=8,8, 8,8 Hz), 7,31-7,41 (2H, m), 7,63 (2H, DD, J=5.0 and an 8.8 Hz), 7,83 (1H, DD, J=2,4, 13,0 Hz), 8,01 (1H, m), with 8.05 (1H, d, J=5.8 Hz), 9,10 (1H, c), 10,26 (1H, c), 10,51 (1H, c).

ESI-MS (m/z): 555 [M+H]+.

Example 119

N-(4-{2-[3-(3-Dimethylaminopropyl)-3-methylurea]pyridine-4-yloxy}-2-were}-N'-(4-forfinal)malonamide

Specified in the title compound (7.4 mg, 8.6 percent) receive in the form of a colorless powder of N-[4-(2-aminopyridine-4-yloxy)-2-were]-N'-(4-forfinal)malonamide (60 mg), triethylamine (0,042 ml), phenylcarbamate (0,038 ml) and N,N-diethyl-N'-methylpropan-1,3-diamine (br93.1 mg).

Range1H-NMR (DMSO-d6) δ (ppm): 0,97 (6H, t, J=7.0 Hz), 1,68 (2H, m), and 2.26 (3H, c), a 2.36 (2H, m), 2,53 (2H, m), 2,80 (3H, c), and 3.31 (4H, m), and 3.2 (2H, c)6,50 (1H, DD, J=2,4, 5,6 Hz), of 6.96 (1H, d, J=2,4, 8,8 Hz),? 7.04 baby mortality (1H, d, J=2.4 Hz), 7,17 (2H, DD, J=9,2, 9,2 Hz), 7,35 (1H, d, J=2.4 Hz), EUR 7.57 (1H, d, J=8,8 Hz), to 7.64 (2H, DD, J=5,2, 9,2 Hz), of 8.06 (1H, d, J=5.6 Hz), for 9.64 (1H, c), 10,02 (1H, Sirs), 10,27 (1H, c).

ESI-MS (m/z): 565 [M+H]+.

Example 120

N-[4-(2-Acetaminophen-4-yloxy)-2-were]-N'-(4-forfinal)malonamide

Specified in the header of the connection (by 33.7 mg, 51%) was obtained as colorless crystals from N-[4-(2-aminopyridine-4-yloxy)-2-were]-N'-(4-forfinal)malonamide (60 mg), triethylamine (0,027 ml) and acetylchloride (0,053 ml).

Range1H-NMR (DMSO-d6) δ (ppm): 2,04 (3H, c), and 2.26 (3H, c), 3,53 (2H, c), only 6.64 (1H, d, J=5.6 Hz), of 6.99 (1H, d, J=8,2 Hz), 7,07 (1H, c), 7,17 (2H, DD, J=8,6, 8.6 Hz), 7,58 (1H, d, J=8,2 Hz), 7,62-7,66 (3H, m), 8,17 (1H, d, J=5.6 Hz), 9,65 (1H, c), 10,27 (1H, c), 10,53 (1H, c).

ESI-MS (m/z): 459 [M+Na]+.

Example 121

N-(4-Forfinal)-N'-(3-methyl-4-{2-[(Morpholine-4-carbonyl)amino]pyridine-4-yloxy}phenyl)malonamide

Specified in the title compound (14 mg, 18%) was obtained as colorless powder from morpholine-4-carboxylic acid [4-(4-amino-2-methylphenoxy)pyridine-2-yl]amide (50 mg), N-(4-forfinal)malonic acid (90 mg) and hexaflurophosphate (1H-1,2,3-benzotriazol-1 iloxi)[three(dimethylamino)]phosphonium (202 mg).

Range1H-NMR (DMSO-d6) δ (ppm): 2,08 (3H, c), 3,39 (4H, m), 3,47 (2H, c), 3,53 (4H, m), 6,51 (1H, m), 7,05 (1H, d, J=9,2 Hz), 7,16 (2H, DD, J=9,0, 9.0 Hz), 7,26 (1H, c), 7,51 (1H, m), to 7.61-the 7.65 (3H, m), of 8.09 (1H, d, J=6,0 Hz), 9,20 (1H, c), 10,23 (2H, c).

ESI-MS (m/z): 508 [M+H]+.

Example 122

N(4-Forfinal)-N'-(3-methyl-4-{2-[(pyrrolidin-1-carbonyl)amino]pyridine-4-yloxy}phenyl)malonamide

Specified in the title compound (27 mg, 34%) was obtained as colorless powder from pyrrolidin-1-carboxylic acid [4-(4-amino-2-methylphenoxy)pyridine-2-yl]amide (50 mg), N-(4-forfinal)malonic acid (95 mg) and hexaflurophosphate (1H-1,2,3-benzotriazol-1 iloxi)[three(dimethylamino)]phosphonium (212 mg).

Range1H-NMR (DMSO-d6) δ (ppm): 1,80 (4H, m), of 2.08 (3H, c), up 3.22 (4H, m), 3,47 (2H, c), of 6.50 (1H, DD, J=8,8 Hz),? 7.04 baby mortality (1H, DD, J=8,8 Hz), 7,16 (1H, DD, J=8,8, 8,8 Hz), was 7.36 (1H, d, J=2.4 Hz), 7,51 (2H, DD, J=2,4, 8,8 Hz), 7,60-the 7.65 (3H, m), 8,07 (1H, d, J=6.0 Hz), 8,61 (1H, c), 10,23 (2H, c).

ESI-MS (m/z): 492 [M+H]+.

Example 123

N-(4-{2-[3-(3-Diethylaminoethyl)ureido]pyridine-4-yloxy}-2-chlorophenyl)-N'-(4-forfinal) malonamide

Specified in the header connection (79,7 mg, 56.3 per cent) receive in the form of a powder pale yellow color of 1-[4-(4-amino-3-chlorophenoxy)pyridine-2-yl]-3-(2-diethylaminoethyl)urea (95,9 mg), N-(4-forfinal)malonic acid (150 mg), triethylamine (0,106 ml) and hexaflurophosphate (1H-1,2,3-benzotriazol-1 iloxi)[three(dimethylamino)]phosphonium (337 mg).

Range1H-NMR (DMSO-d6) δ (ppm): 1,00 (6H, t, J=7.2 Hz), 2,49-2,52 (6H, m), 3,19-is 3.21 (2H, m), 3,61 (2H, m), 6,56 (1H, DD, J=2,4, 5,6 Hz)6,91 (1H, c), 7,10-of 7.25 (3H, m), the 7.43 (1H, d, J= 2.4 Hz), 7,63 (2H, DD, J=5, 7 Hz), 7,99 shed 8.01 (1H, m), 8,07 (1H, d, J=6.0 Hz), to 8.20 (1H, m), 9,24 (1H, Sirs), of 10.05 (1H, c), 10,30 (1H, c).

Example 124

N-(2-Chloro-4-{2-[3-(3-morpholine-4-ylpropyl)ureido]pyridine-4-yloxy}phenyl)-N'-(4-forfinal)malonamide

Specified in the header connection (90,1 mg, 62.4 per cent) gender is given in the form of a white powder of 1-[4-(4-amino-3-chlorophenoxy)pyridine-2-yl]-3-(3-morpholine-4-ylpropyl)urea (100 mg), N-(4-forfinal)malonic acid (146 mg), triethylamine (0,103 ml) and hexaflurophosphate (1H-1,2,3-benzotriazol-1 iloxi)[three(dimethylamino)]phosphonium (328 mg).

Range1H-NMR (DMSO-d6) δ (ppm): 1,59 (2H,m), 2,22-to 2.40 (6H, m)and 3.15 (2H, m), of 3.56 (4H, m), 3,62 (2H, m), to 6.57 (1H, DD, J=2,0,6,0 Hz)6,94 (1H, m), 7,10-of 7.25 (3H, m), the 7.43 (1H, d, J=2,8 Hz), 7,55-of 7.70 (2H, m), 7,99-of 8.06 (2H,, m), 8,08 (1H, d, J=6.0 Hz), 9,13 (1H, c), of 10.05 (1H, Sirs), 10,30 (1H, Sirs).

Example 125

N-[2-Chloro-4-(2-{3-[3-(4-methylpiperazin-1-yl)propyl]ureido}pyridine-4-yloxy)phenyl]-N'-(4-forfinal)malonamide

Specified in the header connection (79,7 mg, 55.8 per cent) receive in the form of a white powder of 1-[4-(4-amino-3-chlorophenoxy)pyridine-2-yl]-3-[3-(4-methylpiperazin-1-yl)propyl]urea (100 mg), N-(4-forfinal)malonic acid (151 mg), triethylamine (0,107 ml) and hexaflurophosphate (1H-1,2,3-benzotriazol-1 iloxi)[three(dimethylamino)]phosphonium (339 mg).

Range1H-NMR (DMSO-d6) δ (ppm): was 1.58 (2H, m)to 2.18 (3H, m), 2,22-2,48 (10H, m), 3,14 (2H, m), 3,61 (2H, m), to 6.57 (1H, DD, J=2,4, 6,0 Hz)6,94 (1H, m), 7,10-of 7.25 (3H, m), the 7.43 (1H, d, J=2.0 Hz), 7,60-of 7.70 (2H, m), 8,01 (2H,, m), 8,08 (1H, d, J=6.0 Hz), 9,12 (1H, c), 10,06 (1H, m), 10,30 (1H, Sirs).

Example 126

N-[2-Chloro-4-(2-{3-[3-(diethylamino)propyl]ureido}pyridine-4-yloxy)phenyl]-N'-(4-forfinal)malonamide

Specified in the header of the connection (for 70.9 mg, 48.7 per cent) receive in the form of a white powder of 1-[4-(4-amino-3-chlorophenoxy)pyridine-2-yl]-3-(3-(diethylaminopropyl)urea (100 mg), N-(4-forfinal)malonic acid (151 mg), triethylamine (,107 ml) and hexaflurophosphate (1H-1,2,3-benzotriazol-1 iloxi)[three(dimethylamino)]phosphonium (339 mg).

Range1H-NMR (DMSO-d6) δ (ppm): 0,94 (6H, m)of 1.55 (2H, m), 2,46 (3H, m)and 3.15 (2H, m), 3,23 (3H, m), 3,62 (2H, m), to 6.57 (1H, DD, J=2, 5.6 Hz), 6,92 (1H, m), 7,15-7,20 (3H, m), the 7.43 (1H, d, J=2.4 Hz), 7,60-the 7.65 (2H, DD, J=4,8, 8,8 Hz), 8,00 (1H, m), 8,07 (2H, m), 9,14 (1H, c), 10,06 (1H, Sirs), 10,31 (1H, Sirs).

Example 127

N-(3-Fluoro-4-{2-[(pyrrolidin-1-carbonyl)amino]pyridine-4-yloxy}phenyl)-N'-(pyridine-2-yl)malonamic

Specified in the header connection (to 11.9 mg, 14.3 per cent) receive in the form of a solid pale brown color of N-(3-fluoro-4-{2-[(pyrrolidin-1-carbonyl)amino]pyridine-4-yloxy}phenyl)malonic acid (70.0 mg), 2-aminopyridine (16.4 mg), triethylamine (0,0363 ml) and hexaflurophosphate (1H-1,2,3-benzotriazol-1 iloxi)[three(dimethylamino)]phosphonium (116,0 mg).

Range1H-NMR (DMSO-d6) δ (ppm): 1,80 (4H, m), and 3.31 (4H, m), 3,61 (2H, m), 6,60 (1H, m), 7,12 (1H, m), 7,35 (2H, m), 7,46 (1H, c), 7,81 (2H, m), 8,10 (2H, m), with 8.33 (1H, m), to 8.70 (1H, c), 10,49 (1H, c), is 10.68 (1H, c).

Example 128

N-(3-Fluoro-4-{2-[(pyrrolidin-1-carbonyl)amino]pyridine-4-yloxy}phenyl)-N'-(thiophene-2-yl)malonamic

Specified in the header connection (50,1 mg, 59.5 per cent) receive in the form of a white powder of N-(3-fluoro-4-{2-[(pyrrolidin-1-carbonyl)amino]pyridine-4-yloxy}phenyl)malonic acid (70.0 mg), thiophene-2-ylamine (69,4 mg), triethylamine (0,097 ml) and hexaflurophosphate (1H-1,2,3-benzotriazol-1 iloxi)[three(dimethylamino)]phosphonium (77.0 mg).

Range1H-NMR (DMSO-d6) δ (ppm): 1,80 (4H, m), 3.25 to of 3.42 (4H, m), 3,52 (2H, m), 6,60 (1H, DD, J=2,4, 5,6 Hz), of 6.71 (1H, d is, J=1,2, 3,6 Hz)6,86 (1H, DD, J= 3,6, and 5.6 Hz), 6,97 (1H, DD, J=1,2, 5,6 Hz), 7,19 (2H, m), 7,47 (1H, d, J=2.0 Hz), 7,82 (1H, DD, J=2,0, 13,2 Hz), 8,11 (1H, d, J=6.0 Hz), to 8.70 (1H, c), 10,54 (1H, Sirs), 11,40 (1H, Sirs).

Example 129

N-(3-Fluoro-4-{2-[(pyrrolidin-1-carbonyl)amino]pyridine-4-yloxy}phenyl)-N'-methyl-N'-phenylmalonamide

Specified in the header connection (45,4 mg, 53.1 per cent) receive in the form of a white powder of N-(3-fluoro-4-{2-[(Pyrrolidin-1-carbonyl)amino]pyridine-4-yloxy}phenyl)malonic acid (70.0 mg), methylphenylamine (0,0283 ml), triethylamine (0,0243 ml) and hexaflurophosphate (1H-1,2,3-benzotriazol-1 iloxi)[three(dimethylamino)]phosphonium (77.0 mg).

Range1H-NMR (CDCl3) δ (ppm): 1,95 (4H, m), up 3.22 (2H, c), the 3.35 (3H, c), 3,44 (4H, m), 6,53 (1H, DD, J=2.0 a, 6,0 Hz), 7,12 (2H, m), 7,16-7,30 (3H, m), of 7.36-of 7.60 (3H, m), 7,68 (1H, d, J=2.0 Hz), 7,73 (1H, DD, J=2,4, 12 Hz), 8,03 (1H, d, J=6.0 Hz), accounted for 10.39 (1H, Sirs).

Example 130

N-{4-[6-(3,3-Dimethylurea)pyrimidine-4-yloxy]-3-forfinal}-N'-(4-forfinal)malonamide

Specified in the header connection (33,2 mg, 74,0%) are obtained in the form of a solid white color of N-{4-[6-(3,3-dimethylurea)pyrimidine-4-yloxy]-3-forfinal}malonic acid (36,0 mg), 4-ftorhinolona (0,014 ml), triethylamine (0,013 ml) and hexaflurophosphate (1H-1,2,3-benzotriazol-1 iloxi)[three(dimethylamino)]phosphonium (42.2 mg).

Range1H-NMR (CDCl3) δ (ppm): 3,05 (6H, c), 3,53 (2H, c),? 7.04 baby mortality (2H, m), 7,17 (1H, m), 7.23 percent (1H, m), 7,38 (1H, Sirs), 7,46-7,56 (2H, m), 7,63 (1H, m), of 7.70 (1H, DD, J=2,4, 12.0 Hz), 8,35 (1H, m), 8,82 (1H, Sirs), a 9.25 (1H, Sirs).

The use of the 131

N-(4-Forfinal)-N'-(3-fluoro-4-{6-[(pyrrolidin-1-carbonyl)amino]pyrimidine-4-yloxy}phenyl)malonamide

Specified in the header connection (to 68.0 mg, 86.7 per cent) receive in the form of a solid pale brown color of 4-(4-amino-2-pertenece)-6-[(pyrrolidin-1-yl)carbylamine]pyridine (50 mg), N-(4-forfinal)malonic acid (93,5 mg), triethylamine (of 0.066 ml) and hexaflurophosphate (1H-1,2,3-benzotriazol-1 iloxi)[three(dimethylamino)]phosphonium (210 mg).

Range1H-NMR (DMSO-d6) δ (ppm): to 1.83 (4H, m), 3,32-of 3.48 (4H, m), 3,49 (2H, c), 7,17 (2H, m), 7,34 (2H, m), 7,45 (1H, c), 7,63 (2H, DD, J=5,9 Hz), to 7.77 (1H, m), 8,39 (1H, c), 9,39 (1H, Sirs), 10,26 (1H, Sirs), of 10.47 (1H, Sirs).

Example 132

N-(2,4-Differenl)-N'-(3-fluoro-4-{6-[(Pyrrolidin-1-carbonyl)amino]pyrimidine-4-yloxy}phenyl)malonamide

Specified in the header connection (74,3 mg, 91.4 per cent) receive in the form of a solid pale brown color of 4-(4-amino-2-pertenece)-6-[(pyrrolidin-1-yl)carbylamine]pyridine (50 mg), N-(2,4-differenl)malonic acid (102 mg), triethylamine (of 0.066 ml) and hexaflurophosphate (1H-1,2,3-benzotriazol-1 iloxi)[three(dimethylamino)]phosphonium (210 mg).

Range1H-NMR (DMSO-d6) δ (ppm): to 1.83 (4H, Sirs), to 3.41 (4H, Sirs), to 3.58 (2H, c), was 7.08 (1H, m), 7,34 (3H, m), 7,46 (1H, c), 7,76 (1H, m), to 7.93 (1H, m), 8,40 (1H, c), 9,40 (1H, c), 10,04 (1H, Sirs), of 10.47 (1H, Sirs).

Example 133

N-(2,4-Differenl)-N'-{4-[6-(3,3-dimethylurea)pyrimidine-4-yloxy]-3-forfinal}malonamic

Specified in the header of the giving (5.4 mg, 10,7%) are obtained in the form of a solid pale yellow color of 1-[4-(4-amino-2-pertenece)pyrimidine-6-yl]-3-dimethyloxetane (30 mg), N-(2,4-differenl)of malonic acid to 66.5 mg), triethylamine (0,043 ml) and hexaflurophosphate (1H-1,2,3-benzotriazol-1 iloxi)[three(dimethylamino)]phosphonium (137 mg).

Range1H-NMR (DMSO-d6) δ (ppm): 2,94 (6H, c)to 3.58 (2H, c), to 7.09 (1H, m), 7,25-7,42 (4H, m), 7,76 (1H, m), 7,92 (1H, m), 8,40 (1H, m), to 9.57 (1H, Sirs), 10,04 (1H, Sirs), of 10.47 (1H, Sirs).

Example 134

N-(4-Forfinal)-N'-(3-fluoro-4-(6-{[4-(pyrrolidin-1-yl)piperidine-1-carbonyl]amino}pyrimidine-4-yloxy)phenyl]malonamic

Specified in the header connection (31,0 mg, 71.4 per cent) receive in the form of a solid pale yellow color of 4-(pyrrolidin-1-yl)piperidine-1-carboxylic acid [6-(4-amino-2-pertenece)pyrimidine-4-yl]amide (30 mg), N-(4-forfinal)malonic acid (30 mg), triethylamine (0,021 ml) and hexaflurophosphate (1H-1,2,3-benzotriazol-1 iloxi)[three(dimethylamino)]phosphonium (66 mg).

Range1H-NMR (CDCl3) δ (ppm): 1,45-to 1.60 (2H, m), of 1.80 (4H, m), a 1.96 (2H, m), 2,18-of 2.28 (1H, m), 2,58 (4H, m), 3.04 from (2H, m), 3,53 (2H, c), was 4.02 (2H, m), 7,05 (2H, m), 7,16 (1H, m), 7,20 (1H, m), the 7.43 (1H, Sirs), 7,51 (2H,, m), 7,58 (1H, c), of 7.70 (1H, DD, J=2, 12 Hz), a 8.34 (1H, m), 8,76 (1H, Sirs), 9,20 (1H, Sirs).

Example 135

N-(4-{6-[([1,4']Bipyridinyl-1'-carbonyl)amino]pyrimidine-4-yloxy}-3-forfinal)-N'-(4-forfinal)malonamide

Using [1,4']bipyridinyl-1'-carboxylic acid [6-(2-fluoro-4-nitrophenoxy)pyrimidine-4-yl]amide (43 what g) and 10% palladium on coal (21 mg), get raw [1,4']bipyridinyl-1'-carboxylic acid [6-(4-amino-2-pertenece)pyrimidine-4-yl]amide. Using the crude N-(4-forfinal)malonic acid (38 mg), triethylamine (0,027 ml) and hexaflurophosphate (1H-1,2,3-benzotriazol-1 iloxi)[three(dimethylamino)]phosphonium (85 mg), get mentioned in the title compound (28.8 mg, 50.2 per cent) in the form of a solid white color.

Range1H-NMR (CDCl3) δ (ppm): 0,89 (2H, m)of 1.26 (2H, m), 1,38-of 1.78 (5H, m), 1,90 (2H, m), 2,44-2,62 (4H, m), of 2.92 (2H, m), 3,53 (2H, c), 4,14 (2H, m), 7,05 (2H, m), 7,17 (1H, m), 7.23 percent (1H, m), 7,44 (1H, Sirs), 7,51 (2H,, m), 7,60 (1H, c), of 7.70 (1H, m), a 8.34 (1H, Sirs), 8,72 (1H, Sirs), 9,18 (1H, Sirs).

ESI-MS (m/z): 594 [M+H]+.

Example 136

N-(4-Forfinal)-N'-[4-(2-{[4-(pyrrolidin-1-yl)piperidine-1-carbonyl]amino}pyridine-4-yloxy)phenyl]malonamic

Specified in the header connection (to 22.6 mg, 51,3%) are obtained in the form of a solid white color of 4-(4-aminophenoxy)-2-{[4-(pyrrolidin-1-yl)piperidine-1-yl]carbylamine}pyridine (30 mg), N-(4-forfinal)malonic acid (31 mg), triethylamine (0,016 ml) and hexaflurophosphate (1H-1,2,3-benzotriazol-1 iloxi)[three(dimethylamino)]phosphonium (69 mg).

Range1H-NMR (CDCl3) δ (ppm): 1,50 (2H, m)to 1.79 (4H, m), with 1.92 (2H, m), of 2.20 (1H, m), of 2.56 (4H, m), 2,96 (2H, m), 3,51 (2H, m), 3,98 (2H, m), to 6.58 (1H, m), of 6.96-7,10 (4H, m), 7,33 (1H, m), 7,44-7,66 (5H, m), of 8.04 (1H, d, J=6.0 Hz), 8,98-9,18 (2H, m).

Example 137

N-(4-{2-[([1,4']bipyridinyl-1'-carbonyl)amino]pyridine-4-yloxy}phenyl)-N'-(4-forfinal)malonamide

Specified in the title compound, or 37.9 mg, 86.9%of) get in a solid white color of 4-(4-aminophenoxy)-2-{[4-(piperidine-1-yl)piperidine-1-yl]carbylamine}pyridine (30 mg), N-(4-forfinal)malonic acid (30 mg), triethylamine (0,021 ml) and hexaflurophosphate (1H-1,2,3-benzotriazol-1 iloxi)[three(dimethylamino)]phosphonium (67 mg).

Range1H-NMR (CDCl3) δ (ppm): 0,88 (2H, m), 1.27mm (2H, m), of 1.35 and 1.75 (5H, m), of 1.85 (2H, m), a 2.36-of 2.54 (4H, m), 2,85 (2H, m), 3,44-of 3.54 (2H, m), 4.09 to (2H, m), 6,56 (1H, DD, J=2,4, 6,0 Hz),6,94-7,10 (4H, m), 7,30 (1H, m), 7,45-to 7.64 (5H, m), of 8.04 (1H, d, J=6.0 Hz), 9,01 (2H, Sirs).

Example 138

N-(4-{2-[3-(3-Diethylaminopropyl)-3-methylurea]pyridine-4-yloxy}phenyl)-N'-(4-forfinal)malonamide

Using [4-(4-nitrophenoxy)pyridine-2-yl]carbamino acid phenyl ester (60 mg) and N,N-diethyl-N'-methylpropan-1,3-diamine (98,6 mg), get the crude 3-[4-(4-nitrophenoxy)pyridine-2-yl]-1-(3-diethylaminopropyl)-1-metalmachine. The crude product (69 mg) is subjected to catalytic hydrogenation using 10% palladium on coal (72 mg) and get the crude 3-[4-(4-aminophenoxy)pyridine-2-yl]-1-(3-diethylaminopropyl)-1-metalmachine. Using this connection (63.5 mg), N-(4-forfinal)malonic acid (67 mg), triethylamine (0,048 ml) and hexaflurophosphate (1H-1,2,3-benzotriazol-1 iloxi)[three(dimethylamino)]phosphonium (151 mg), get mentioned in the title compound, or 37.9 mg, 86.9 per cent) in the form of a solid white color.

Spec is R 1H-NMR (CDCl3) δ (ppm): of 1.06 (6H, t, J=7.2 Hz), of 1.78 (2H, m), of 2.51 (2H, m), 2,60-by 2.73 (4H, m), of 2.86 (3H, c), to 3.38 (2H, t, J=6.4 Hz), 3,48 (2H, Sirs), 6,55 (1H, m), 6,98 (2H, m),? 7.04 baby mortality (2H, m), the 7.43 (1H, Sirs), 7,46-a 7.62 (4H, m), 7,71 (1H, DD, J=3.2, and 5.6 Hz), with 8.05 (1H, d, J=5.6 Hz), of 9.21 (2H, Sirs).

Example 139

N-{4-[6-(3,3-Dimethylurea)pyrimidine-4-yloxy]-3-forfinal}-N'-(4-forfinal)malonamide

Specified in the header connection (33,2 mg, 74,0%) are obtained in the form of a solid white color of N-{4-[6-(3,3-dimethylurea)pyrimidine-4-yloxy]-3-forfinal}malonic acid (36,0 mg), 4-ftorhinolona (0,014 ml), triethylamine (0,013 ml) and hexaflurophosphate (1H-1,2,3-benzotriazol-1 iloxi)[three(dimethylamino)]phosphonium (42.2 mg).

Range1H-NMR (CDCl3) δ (ppm): 3,05 (6H, c), 3,53 (2H, c),? 7.04 baby mortality (2H, m), 7,17 (1H, m), 7.23 percent (1H, m), 7,38 (1H, Sirs), 7,46-7,56 (2H, m), 7,63 (1H, m), of 7.70 (1H, DD, J=2,4, 12.0 Hz), 8,35 (1H, m), 8,82 (1H, Sirs), a 9.25 (1H, Sirs).

Example 140

1-(4-{3-Chloro-4-[3-(2-phenylacetyl)touraid]phenoxy}pyridine-2-yl)-3-determation

Range1H-NMR (DMSO-d6) δ (ppm): of 1.05 (6H, t, J=7.2 Hz), 3,20-of 3.60 (4H, m), a-3.84 (2H, c), is 6.61 (1H, DD, J=2,0, 5.6 Hz), 7,20 (1H, DD, J=2,8, 8,8 Hz), 7,20-7,40 (5H, m), 7,45 (1H, d, J=2.4 Hz), 7,53 (1H, c), of 8.06 (1H, d, J=8,8 Hz), 8,16 (1H, d, J=5.6 Hz), 8,77 (1H, c), 11,90 (1H, c), 12,37 (1H, c).

Example 141: 4-{3-Chloro-4-[3-(2-phenylacetyl)touraid]phenoxy}-2-[(4-methylpiperazin-1-yl)carbylamine]pyridine

Range1H-NMR (CDCl3) δ (ppm): 2,32 (3H, c), 2,40 at 2.45 (4H, m), 3,49-of 3.54 (4H, m), 3,81 (2H, c), 6,48 (1H, DD, J=2,4, 5,6 Hz), 6,99-7,07 (2H, m), 7,20-of 7.60 (7H, m), 7,68 (1H, d, J=2.4 Hz), and 8.0 (1H, d, J=5.6 Hz), to 8.41 (1H, d, J=8,8 Hz), 8,51 (1H, Sirs).

ESI-MS (m/z): 561 [M+Na]+

Example 142

4-{3-Chloro-4-[3-(2-phenylacetyl)touraid]phenoxy}-2-[(1-methylpiperidin-4-yl)carbylamine]pyridine

Range1H-NMR (DMSO-d6) δ (ppm): 1,50-1,90 (6H, m)to 2.13 (3H, c), is 2.41 (1H, m), 2,75-and 2.79 (2H, m), 3,85 (2H, c), of 6.71 (1H, m), 7,20-7,40 (6H, m), of 7.48 (1H, m), 7,74 (1H, m), 8,07 (1H, d, J=8,8 Hz), 8,23 (1H, d, J=5.6 Hz), 10,54 (1H, c), 11,90 (1H, Sirs), KZT 12.39 (1H, Sirs).

Example 143

4-{3-Chloro-4-[3-(2-phenylacetyl)touraid]phenoxy}-2-(ethoxycarbonyl)pyridine

Range1H-NMR (DMSO-d6) δ (ppm): of 1.20 (3H, t, J=7.2 Hz), a-3.84 (2H, c), 4,10 (2H, q, J=7.2 Hz), of 6.66 (1H, DD, J=2,0, 5.6 Hz), 7,22 (1H, DD, J=2,4, 8,8 Hz), 7,28-7,40 (5H, m), 7,44 (1H, d, J=2.0 Hz), of 7.48 (1H, d, J=2.4 Hz), 8,08 (1H, d, J=8,8 Hz), 8,18 (1H, d, J=5.6 Hz), 10,23 (1H, c), 11,91 (1H, c), KZT 12.39 (1H, c).

Example 144

4-{3-Methoxy-4-[3-(2-phenylacetyl)touraid]phenoxy}-2-[(pyrrolidin-1-yl)carbylamine]pyridine

Range1H-NMR (DMSO-d6) δ (ppm): 1,70-1,90 (4H, m), 3,20-3,40 (4H, m in), 3.75 (2H, c), 3,83 (3H, c), 6,56 (1H, DD, J=2,4, 6,0 Hz), to 6.67 (1H, DD, J=2,4, 8,8 Hz), make 6.90 (1H, d, J=2.4 Hz), 7,20-7,40 (6H, m), 7,49 (1H, d, J=2,4 Hz), to 7.95 (1H, d, J=8,8 Hz), of 8.09 (1H, m)8,64 (1H, c), a 9.35 (1H, c).

Example 145

4-{3-Methoxy-4-[3-(2-phenylacetyl)touraid]phenoxy}-2-[(morpholine-4-yl)carbylamine]pyridine

Range1H-NMR (CDCl3) δ (ppm): 3,40-to 3.50 (4H, m), 3,70 (3H, c), 3,65 of 3.75 (4H, m), of 3.77 (2H, c), of 6.49 (1H, DD, J=2,4, 6,0 Hz), to 6.58 (1H, d, J=2.4 Hz), to 6.67 (1H, DD, J=2.0 a, 8,8 Hz), 7.23 percent (1H, Sirs), 7,30 was 7.45 (6H, m), to 7.59 (1H, Sirs), of 7.70 (1H, Sirs), 8,01 (1H, d, J=6.0 Hz), at 8.36 (1H, d, J=8.8 Hz).

Example 146

4-{4-[3-(2-Phenylacetyl)touraid]phenyl}amino-6-[(pyrrolidin-1-yl)carbylamine]pyrimidine

Range1H-NMR (DMSO-d6) δ (ppm): 1,80-2,00 (4H, m), 3.00 and-of 3.60 (4H, m), 3,81 (2H, c), 7,20 is 7.50 (6H, m), 7,51 (2H, d, J=8,8 Hz), to 7.64 (2H, d, J=8,8 Hz), 8,32 (1H, c), a total of 8.74 (1H, c), of 9.55 (1H, c), 11,65 (1H, c), 10,31 (1H, c).

Example 147

2-[(Dimethylamino)carbylamine]-4-{2-fluoro-3-[2-(tert-butyl)acetylthio]obeidience}pyridine

Range1H-NMR (DMSO-d6) δ (ppm): 1,04 (9H, c), of 2.38 (2H, c), 2,90 (6H, c), is 6.61 (1H, DD, J=2,4, 6,0 Hz), of 7.36-the 7.43 (2H, m), 7,54 (1H, m), with 8.05 (1H, DD, J=2,4, 8,8 Hz), 8,13 (1H, d, J=6.0 Hz), to 8.94 (1H, c), 11,47 (1H, c), 12,72 (1H, c).

Example 148

1-{4-[3-Chloro-4-(3-phenylacetylamino)phenoxy]pyridine-2-yl}-3-[3-(morpholine-4-yl)propyl]urea

Range1H-NMR (DMSO-d6) δ (ppm): 1,59 (2H, m), 2,27-of 2.36 (6H, m), and 3.16 (2H, m), of 3.56 (4H, m), 3,85 (2H, c), 6,56 (1H, d, J=5.6 Hz), 7,00 (1H, c), 7,21 (1H, d, J=9,2 Hz), 7,29 (1H, m), 7,35 (4H, m), 7,47 (1H, c), 8,02 (1H, m), of 8.09 (2H, m), 9,17 (1H, c), 11,91 (1H, Sirs), KZT 12.39 (1H, Sirs).

Example 149

1-{4-[3-Chloro-4-(3-phenylacetylamino)phenoxy]pyridine-2-yl}-3-[3-(1-methylpiperazin-4-yl)propyl]urea

Range1H-NMR (DMSO-d6) δ (ppm): 1.57 in (2H, m)to 2.13 (3H, c), 2,29 (10H, m), 3,14 (2H, m), 3,85 (2H, c), 6,56 (1H, DD, J=2,4, 5,6 Hz), of 6.99 (1H, d, J=2.4 Hz), 7,20 (1H, DD, J=2,8, 8,8 Hz), 7,29 (1H, m), 7,35 (4H, m), 7,47 (1H, d, J=2,8 Hz), 8,01 (1H, m), of 8.09 (1H, d, J=8,8 Hz), 8,10 (1H, d, J=5.6 Hz), 9,16 (1H, c), 11,91 (1H, Sirs), KZT 12.39 (1H, Sirs).

ESI-MS (m/z): 596 [M+H]+.

Example 150

1-{4-[3-Chloro-4-(3-phenylacetylamino)phenoxy]pyridine-2-yl}-3-(3-diethylaminopropyl)ureas of the Sabbath.

Range1H-NMR (DMSO-d6) δ (ppm): to 0.94 (6H, t, J=7,0 Hz)of 1.55 (2H, m)2,44 (6H, m)and 3.15 (2H, m), 3,85 (2H, c), 6,56 (1H, DD, J=2,4, 5,6 Hz), 6,98 (1H, d, J=2.4 Hz), 7,21 (1H, DD, J=2,8, 8,8 Hz), 7,30 (1H, m), of 7.36 (4H, m), 7,47 (1H, d, J=2,8 Hz), of 8.09 (3H, m), 9,19 (1H, c), 11,91 (1H, Sirs), KZT 12.39 (1H, Sirs).

ESI-MS (m/z): 569 [M+H]+.

Example 151

3-[4-(4-{3-[2-(4-Forfinal)acetyl]touraid}phenoxy)pyridine-2-yl]-1,1-dimethyloxetane

Range1H-NMR (CDCl3) δ (ppm): 3,00 (6H, c), 3,71 (2H, c), 6,51 (1H, DD, J=2,0, 5.6 Hz), 7,03 (2H, m), 7,06-of 7.24 (5H, m), 7,32 (2H, m), 7,47 (2H, m), 7,60 (1H, d, J=2.0 Hz),8,02 (1H, d, J=5.6 Hz).

Example 152

1-(4-{3-Chloro-4-[3-(2-phenylacetyl)touraid]phenoxy}pyridine-2-yl)-3-atilmotin

Range1H-NMR (DMSO-d6) δ (ppm): was 1.04 (3H, t, J=7.2 Hz), of 3.12 (2H, m), 3,82 (2H, c), is 6.54 (1H, DD, J=2,4, 5,6 Hz), 6,99 (1H, c), 7,18 (1H, DD, J=2,8, 8,8 Hz), 7,20-7,40 (5H, m), 7,45 (1H, d, J=2.4 Hz), 7,92 (1H, Sirs), 8,00-8,10 (2H, m), 9,13 (1H, c), 11,89 (1H, c), 12,38 (1H, c).

Example 153

Morpholine-4-carboxylic acid {4-[3-methyl-4-(3-phenylacetylamino)phenoxy]pyridine-2-yl}amide

Range1H-NMR (DMSO-d6) δ (ppm): 2,22 (3H, c), is 3.41 (4H, m), 3,55 (4H, m in), 3.75 (2H, c), 6,56 (1H, DD, J=2,4, a 5.4 Hz), 7,00 (1H, d, J=8,4 Hz), 7,07 (1H, d, J=2.4 Hz), 7,27-7,37 (5H, m), 8,01 (1H, d, J=9,2 Hz), 8,10 (1H, d, J=5.4 Hz), 9,23 (1H, c), 10,48 (1H, c)11,05 (1H, c).

ESI-MS (m/z): 512 [M+Na]+.

Example 154

1-(3-Diethylaminopropyl)-3-{4-[2-methyl-4-(3-phenylacetylamino)phenoxy]pyridine-2-yl}urea

Range1H-NMR (DMSO-d6) δ (ppm): 0,93 (6H, t, J=7.2 Hz), 1,53 (2H, m)to 2.06 (3H, c), of 2.38 (2H, m), 2,43 (4H, q, J=7.2 Hz), of 3.13 (2H, m), 73 (2H, c)6,44 (1H, DD, J=2,0, 5.6 Hz), 6,78 (1H, d, J=2.0 Hz),? 7.04 baby mortality (1H, d, J=8,8 Hz), 7.24 to 7,37 (5H, m), 7,46 (1H, DD, J=2,8, 8,8 Hz), 7,51 (1H, d, J=2,8 Hz), 8,02 (1H, d, J=5.6 Hz), 8,11 (1H, Sirs), 9,07 (1H, c), 10,50 (1H, c), 10,97 (1H, c).

ESI-MS (m/z): 533 [M+H]+.

Example 155

N-(4-Forfinal)-N'-(4-{[2-(dimethylamino)carbylamine]pyridine-4-yloxy}phenyl)deformationand

Range1H-NMR (DMSO-d6) δ (ppm): 2,94 (6H, c), of 6.90 (1H, m), 7,11 (1H, m), 7,20-7,31 (4H, m), 7,72-7,76 (2H, m), 7,86-7,89 (2H, m), to 8.20 (1H, m)11,05 (1H, c), 11,14 (1H, c).

ESI Mass: 488 [M+1]+

Example 156

N-(3-Fluoro-4-{2-[(dimethylamino)carbylamine]pyridine-4-yloxy}phenyl)-N'-(2-phenylethyl)oxalate

Range1H-NMR (DMSO-d6) δ (ppm): 2.91 in (2H, t, J=7.2 Hz), 3,01 (6H, c), the 3.65 (2H, q, J=7.2 Hz), is 6.54 (1H, m), 7,10-7,40 (8H, m), to 7.59 (1H, W), the 7.65 (1H, c), to 7.77 (1H, m), with 8.05 (1H, d, J=5.6 Hz), 9,34 (1H, Sirs).

Example 157

N-(3-Fluoro-4-{2-[(dimethylamino)carbylamine]pyridine-4-yloxy}phenyl)-N'-(3-phenylpropyl)oxalate

Range1H-NMR (DMSO-d6) δ (ppm): 1,96 (2H, Quint, J=7.2 Hz), a 2.71 (2H, t, J=7.2 Hz), 3,01 (6H, c), of 3.42 (2H, q, J=7.2 Hz), is 6.54 (1H, DD, J=2,4, 5,6 Hz), 7,10-7,40 (8H, m), 7,53 (1H, m), 7,66 (1H, d, J=2.4 Hz), 7,78 (1H, DD, J=2,4, 12.0 Hz), with 8.05 (1H, d, J=5.6 Hz), to 9.32 (1H, c).

Example 158

N-(4-Forfinal)-N'-(4-{[2-(pyrrolidin-1-ylcarbonyl)amino]pyridine-4-yloxy}-2-triptoreline)malonamide

Range1H-NMR (CDCl3) δ (ppm): of 1.88 (4H, m), 3,37 (4H, m), 3,49 (2H, c), 6,46 (1H, d, J=5.4 Hz), 6,94 (2H, m), 7,10 (1H, m), 7,20 (1H, m), 7,29 (1H, c), the 7.43 (2H, DD, J=4,8, 8.0 Hz), to 7.64 (1H, c), of 7.97 (1H, d, J=8,8 Hz), to 7.99 (1H, d, J=5.4 Hz), 8,81 (1H, c), of 9.21 (1H, c).

SI-MS (m/z): 546 [M+H] +, 568 [M+Na]+.

Example 159

N-{4-[2-(Cyclopropanecarbonyl)pyridine-4-yloxy]-2-triptoreline}-N'-(4-forfinal)malonamide

Range1H-NMR (DMSO-d6) δ (ppm): 0,78 (4H, m)of 1.23 (1H, m), of 3.56 (2H, c), of 6.73 (1H, d, J=5.4 Hz), 7,16 (2H, m), 7,49-7,63 (4H, m), 7,68 (1H, c), 7,76 (1H, d, J=8,4 Hz), by 8.22 (1H, d, J=5.4 Hz), there is a 10.03 (1H, c), 10,27 (1H, c)10,90 (1H, c).

ESI-MS (m/z): 517 [M+H]+, 539 [M+Na]+.

Example 160

N-{2-Chloro-4-[2-(3-cyclopropylamino)pyridine-4-yloxy]phenyl}-N'-(4-forfinal)malonamide

Range1H-NMR (DMSO-d6) δ (ppm): 0,40 at 0.42 (2H, m), and 0.61-of 0.64 (2H, m), 2,53-of 2.56 (1H, m), 3,62 (2H, m), to 6.57 (1H, DD, J=2,4, 5,6 Hz), 7,01 (1H, m), 7,14-7,20 (3H, m), the 7.43 (1H, d, J=2.4 Hz), to 7.61-to 7.64 (3H, m), 8,01 (1H, d, J=9,2 Hz), 8,08 (1H, d, J=5.6 Hz), 9,03 (1H, c), 10,06 (1H, c), 10,30 (1H, c).

Example 161

N-(2-Chloro-4-{2-[(1-methylpiperidin-4-carbonyl)amino]pyridine-4-yloxy}phenyl)-N'-(4-forfinal)malonamide

Range1H-NMR (DMSO-d6) δ (ppm): 1,48-of 1.62 (2H,m), by 1.68 (2H, m), of 1.80 (2H, m), 2,12 (3H, c), 2,39 (1H, m), 2,58 (1H, m), was 2.76 (2H, m), of 3.78 (1H, m), of 6.71 (1H, DD, J=2,4, 5,6 Hz), 7,13-of 7.23 (3H, m), the 7.43 (1H, m), 7,55-7,72 (3H, m), of 7.96 (1H, m), 8,15 (1H, d, J=5.6 Hz), 9,71 (1H, d, J=12 Hz), 10,32 (1H, Sirs), 10,52 (1H, c).

Example 162

N-Cyclopropyl-N'-(3-fluoro-4-{2-[(pyrrolidin-1-carbonyl)amino]pyridine-4-yloxy}phenyl)malonamide

Range1H-NMR (DMSO-d6) δ (ppm): 0,42 (2H, m)to 0.63 (2H, m), of 1.80 (4H, m), 2,65 (1H, m), 3,21 (2H, m), of 3.25 to 3.45 (4H, m), 6,59 (1H, DD, J=2,4, 5,6 Hz), 7,33 (2H, m), 7,46 (1H, d, J=2.4 Hz), 7,81 (1H, DD, J=2,4, 13 Hz), 8,10 (1H, d, J=5.6 Hz), 8,18 (1H, d, J=4.0 Hz), 8,69 (1H, c), 10,41 (1H, Sirs).

Example 163

N-{-[6-(3,3-Dimethylurea)pyrimidine-4-yloxy]-3-forfinal}-N'-methyl-N'-phenylmalonamide

Range1H-NMR (CDCl3) δ (ppm): a 3.06 (6H, c), up 3.22 (2H, c), the 3.35 (3H, c), 7,10-7,30 (4H, m), 7,32 (1H, Sirs), 7,38 was 7.45 (1H, m), 7,45-7,52 (2H, m), of 7.64 (1H, c), 7,73 (1H, DD, J=2,4, 12.0 Hz), 8,35 (1H, m), the 10.40 (1H, Sirs).

Example 164

N-(3-Fluoro-4-{6-[(Pyrrolidin-1-carbonyl)amino]pyrimidine-4-yloxy}phenyl)-N'-methyl-N'-phenylmalonamide

Range1H-NMR (DMSO-d6) δ (ppm): to 1.83 (4H, Sirs), 3,21 (5H, Sirs), 3,25-3,55 (4H, m), 7,10-of 7.55 (8H, m), 7,68 (1H, m), 8,39 (1H, Sirs), 9,39 (1H, Sirs), 10,19 (1H, Sirs).

Example 165

N-(4-Forfinal)-N'-(4-{2-[(pyrrolidin-1-yl)carbylamine]pyridine-4-ylamino}phenyl)malonamide

Range1H-NMR (DMSO-d6) δ (ppm): 1,70-1,90 (4H, m), 3,20-3,40 (4H, m), of 3.45 (2H, c), 6,47 (1H, m), 7,00-7,20 (4H, m), 7,40-of 7.70 (5H, m), 7,83 (1H, d, J=6.0 Hz), 8,16 (1H, c), 8,63 (1H, c), 10,13 (1H, c), 10,23 (1H, c).

Example 166

1-{6-[2-Fluoro-4-(3-phenylacetylamino)phenoxy]pyrimidine-4-yl}-3-(1-methylpiperidin-4-yl)urea

[6-(2-Fluoro-4-nitrophenoxy)pyrimidine-4-yl]carbamino acid phenyl ester (190 mg) was dissolved in N,N-dimethylformamide (2 ml), then add 4-amino-1-methylpiperidin (176 mg) - N,N-dimethylformamide (3 ml) and stirred for 4 hours. The reaction mixture is distributed between ethyl acetate (30 ml) and saturated aqueous sodium hydrogen carbonate (20 ml). The organic layer was washed with saturated aqueous sodium hydrogen carbonate (20 ml), water (20 ml) and saturated saline (20 ml), then dried over anhydrous sodium sulfate. Dissolve the al evaporated, receiving the crude 1-[6-(2-fluoro-4-nitrophenoxy)pyrimidine-4-yl]-3-(1-methylpiperidin-4-yl)urea (200 mg). The crude product (200 mg) is dissolved in methanol (5 ml) - tetrahydrofuran (5 ml), and then in a nitrogen atmosphere, add 10% palladium on coal (109 mg), after which the nitrogen in the system is replaced with hydrogen and stirred overnight. After replacing the nitrogen in the system, the catalyst is filtered off and washed with ethanol. The filtrate is concentrated under reduced pressure, obtaining a residue which is suspended in a mixture of diethyl ether (2.5 ml) - hexane (5.0 ml). The solid is filtered off and dried in air stream, receiving the crude 1-[6-(4-amino-2-pertenece)pyrimidine-4-yl]-3-(1-methylpiperidin-4-yl)urea (183 mg).

2-phenylacetylamino (36,6 mg) in a nitrogen atmosphere add potassium thiocyanate (53,8 mg) and acetonitrile (3 l), followed by stirring at 60°C for 2 hours. The reaction mixture is cooled to room temperature, then add ethyl acetate (20 ml) and saturated aqueous sodium hydrogen carbonate solution (20 ml) followed by stirring for 30 minutes After distribution solution the organic layer was separated and washed with saturated aqueous sodium hydrogen carbonate (20 ml), water (20 ml) and saturated saline (20 ml) in this order, then dried over anhydrous sodium sulfate. The solvent is evaporated, olucha phenylacetonitrile in the form of a yellow oil.

1-[6-(4-Amino-2-pertenece)pyrimidine-4-yl]-3-(1-methylpiperidin-4-yl)urea (50 mg) is dissolved in ethanol, then add D-10-camphorsulfonic acid (64,6 mg) and stirred for 5 minutes Add the solution phenylacetonitrile in toluene (1.5 ml) and stirred for 4 hours. The reaction mixture is distributed between ethyl acetate (30 ml) and saturated aqueous sodium hydrogen carbonate (20 ml). The organic layer was washed with saturated aqueous sodium hydrogen carbonate (20 ml), water (20 ml) and saturated saline (20 ml), then dried over anhydrous sodium sulfate. The solvent is evaporated and get the remainder, which is purified column chromatography on silica gel (Fuji Silysia NH, eluent: ethyl acetate). The fractions containing the target compound, concentrate, and get the remainder, which is suspended in a mixture of diethyl ether (0.5 ml) - hexane (2.0 ml). The solid is filtered off and dried in a stream of air, getting mentioned in the title compound (13.5 mg, 18.1 per cent) in the form of white powder.

Range1H-NMR (CDCl3) δ (ppm): 1,40-of 1.62 (2H, m), 1,95 is 2.10 (2H, m), of 2.20 (2H, m)to 2.29 (3H, c), is 2.74 (2H, m), 3,76 (2H, c), of 3.80 (1H, m), 6,27 (1H, c), 7,20 (1H, m), 7,25-7,52 (6H, m), 7,86 (1H, DD, J=2,4, and 11.6 Hz), 7,93 (1H, Sirs), scored 8.38 (1H, c), 8,73 (1H, Sirs), 8,96 (1H, m), 12,47 (1H, c).

ESI-MS (m/z): 538 [M+H]+.

The compound of example, receiving 29 also can be synthesized by the following method.

P the emer get 29

3-[4-(4-Amino-2-pertenece)pyridine-2-yl]-1-methyl-1-(1-methylpiperidin-4-yl)urea

After dissolving benzyl ester (3-fluoro-4-{2-[3-methyl-3-(1-methylpiperidin-4-yl)ureido]pyridine-4-yloxy}phenyl)carbamino acid (38,7 mg) in tetrahydrofuran (1.5 ml) and methanol (1.5 ml) is added 10% palladium on coal (16 mg) in a nitrogen atmosphere. The atmosphere in the reaction vessel is replaced with hydrogen and the mixture is stirred for 5 hours at room temperature. The catalyst is filtered off and washed with methanol. The filtrate is concentrated under reduced pressure, obtaining the crude specified in the title compound in the form of oil, pale yellow (28.5 mg).

ESI-MS (m/z): 374 [M+H]+.

Example of getting 29-1

The methyl ester dihydrochloride 4-(4-amino-2-pertenece)pyridine-2-carboxylic acid

After dissolving methyl ester 4-chloropyridin-2-carboxylic acid (30 g) and 2-fluoro-4-NITROPHENOL (41,2 g) in chlorobenzene (24 ml) the reaction mixture is stirred for 4 hours at 120°C in nitrogen atmosphere. The reaction mixture is brought to room temperature, add methanol (100 ml) and the mixture is stirred for 30 minutes. The residue obtained after removal of the solvent under reduced pressure, distributed between ethyl acetate (300 ml) and 1 N. aqueous sodium hydroxide solution (150 ml). The organic layer is separated, washed with 1 N. aqueous solution of Ki is rockside sodium (100 ml) and saturated brine (150 ml), then dried over anhydrous sodium sulfate. The solvent is distilled off under reduced pressure, the obtained residue is added ethanol (200 ml) and the mixture is stirred for 30 minutes. The solid is filtered off and the filtrate is purified column chromatography on silica gel (YMC, SIL-60-400/230W, eluent: heptane:ethyl acetate = 1:1). The fractions containing the target compound are concentrated under reduced pressure, the solid is combined with the previously obtained solid and receive a 4-(2-fluoro-4-nitrophenoxy)pyridine-2-carboxylic acid methyl ester (20,0 g, 40,0%) as a solid pale brown color.

After dissolving the obtained purified product (9,90 g) in methanol (340 ml) and tetrahydrofuran (340 ml) was added 20% palladium hydroxide-carbon (2.4 g) under stirring in nitrogen atmosphere, which is replaced by hydrogen, and the mixture is stirred for 16 hours. Then the atmosphere in the reaction vessel is replaced by nitrogen, the catalyst is filtered off and washed with methanol. After adding to the filtrate a 4 n solution of hydrochloric acid in ethyl acetate (4,18 ml) the mixture was concentrated under reduced pressure, obtaining the crude specified in the title compound in the form of solid pale yellow color (11.5g).

ESI-MS (m/z): 263 [M+H]+.

Example of getting 29-2

4-(4-Benzyloxycarbonylamino-2-pertenece)PI is one-2-carboxylic acid methyl ester

4-(4-Amino-2-pertenece)pyridine-2-carboxylic acid methyl ester (11.5 g) dissolved in acetone (340 ml) and water (170 ml). Then to the reaction mixture is added sodium hydrogen carbonate (17.3 g) under cooling in a bath containing water with ice, add benzylchloride (9,79 ml) and the mixture is stirred for 15 minutes. The reaction mixture was left to warm to room temperature and then stirred for 2 hours. To the reaction mixture add benzylchloride (2,45 ml), cooling in a bath containing ice water, and the mixture is stirred for 18 hours. The residue obtained after concentrating the reaction mixture under reduced pressure, distributed between ethyl acetate (500 ml) and saturated saline (200 ml). The organic layer was separated, washed with water (100 ml) and saturated saline (200 ml) and dried over anhydrous sodium sulfate. The solvent is distilled off under reduced pressure and the resulting solid is suspended in a mixture of ethyl acetate (50 ml) and hexane (30 ml). The solid is filtered off, dried in the air flow and get listed in the title compound (9.6 g, 70.6 per cent) in the form of a solid pale yellow color.

Range1H-NMR (CDCl3) δ (ppm): 3,95-4,10 (3H, m), 5,23 (2H, m), at 6.84 (1H, m), 7,00 (1H, m), 7,11 (2H, m), 7,34-to 7.50 (5H, m), 7,56 (1H, m), a 7.62 (1H, m), 8,59 (1H, m).

Example of getting 29-3

4-(4-Benzyloxycarbonyl the Mino-2-pertenece)pyridine-2-carboxylic acid

After the dissolution of the methyl ester of 4-(4-benzyloxycarbonylamino-2-pertenece)pyridine-2-carboxylic acid (10.7 g) in methanol (450 ml) and N,N-dimethylformamide (150 ml) is added water (75 ml) and lithium hydroxide (1,36 g) and the mixture is stirred for 1 hour at room temperature. After addition of 1 N. hydrochloric acid (100 ml), the reaction mixture was concentrated under reduced pressure, add ethyl acetate (500 ml) for distribution and the precipitated solid is filtered off. The obtained solid is washed with water and hexane and then dried in the air stream. The organic layer obtained filtrate was washed with water (100 ml×2) and saturated saline (200 ml), then dried over anhydrous sodium sulfate. The solvent is distilled off under reduced pressure, the obtained solid is washed with water and hexane and dried in a stream of air. This solid is combined with the previously obtained solid and dried at 60°C during the night, getting listed at the beginning of the connection (at 9.53 g, 92.3 per cent) in the form of white powder.

Range1H-NMR (CDCl3) δ (ppm): of 3.32 (1H, Sirs), 5,19 (2H, c), 7,21 (1H, m), 7,25-7,58 (8H, m), of 7.64 (1H, d, J=12,8 Hz), 8,59 (1H, d, J=5.6 Hz), 10,18 (1H, Sirs).

Example of getting 29-4

[4-(4-Benzyloxycarbonylamino-2-pertenece)pyridine-2-yl]carbamino acid tert-butyl methyl ether

After dissolved the I 4-(4-benzyloxycarbonylamino-2-pertenece)pyridine-2-carboxylic acid (500 mg) in tert-butyl alcohol (5 ml), at room temperature in a nitrogen atmosphere add triethylamine (0,457 ml) and diphenylphosphoryl azide (0,310 ml), after which the mixture is stirred for 1.5 hours. The reaction mixture is heated to 30°C and stirred for 1 hour, then stirred at 40°C for 45 minutes. Then the reaction mixture is heated to 50°C and stirred for 30 minutes, then heated to 60°C and stirred for 30 minutes. After stirring the reaction mixture at 70°C for 30 minutes, it was stirred at 80°C for 30 minutes. Then the reaction mixture is heated to 90°C and stirred for 1.5 hours, after which it is cooled to room temperature and stirred for 15 hours. Then the reaction mixture is distributed between ethyl acetate (50 ml) and saturated aqueous sodium hydrogen carbonate (30 ml). The organic layer was washed with water (30 ml) and saturated saline (30 ml) in that order and dried over anhydrous sodium sulfate. The solvent is distilled off under reduced pressure and then the resulting residue is purified column chromatography on silica gel (Fuji Silysia NH, eluent: heptane:ethyl acetate = 3:2). After concentration under reduced pressure of the fractions containing the target compound, the resulting residue is suspended in a mixture of diethyl ether (3 ml) and hexane (3 ml). Solid otfit byvaut and dried in a stream of air, getting listed in the title compound (277 mg, 46.6%) of in a solid pale yellow color.

Range1H-NMR (CDCl3) δ (ppm): 1,49 (9H, c), with 5.22 (2H, c), 6,46 (1H, DD, J=2.0 a, 6,0 Hz), 6,77 (1H, Sirs), 6,99-7,14 (2H, m), 7,28-of 7.48 (7H, m), 7,52 (1H, m), of 8.06 (1H, d, J=6.0 Hz).

ESI-MS (m/z): 476 [M+Na]+.

Example of getting 29-5

[4-(2-Aminopyridine-4-yloxy)-3-forfinal]carbamino acid benzyl ester

[4-(4-Benzyloxycarbonylamino-2-pertenece)pyridine-2-yl]carbamino acid tert-butyl ester (510 mg) are added to 4 N. the solution of hydrochloric acid in ethyl acetate (30 ml), cooling in a bath containing ice water. The reaction mixture was left to warm to room temperature and then stirred for 16 hours. To the reaction mixture is added diethyl ether (10 ml) and 5 N. aqueous sodium hydroxide solution (1 ml) and stirred for 30 minutes. The organic layer is separated and washed with saturated aqueous sodium hydrogen carbonate (20 ml), water (20 ml) and saturated saline (20 ml), then dried over anhydrous sodium sulfate. The solvent is distilled off under reduced pressure, the obtained residue is purified column chromatography on silica gel (Fuji Silysia NH, eluent: heptane:ethyl acetate = 1:2) and the fractions containing the target compound are concentrated under reduced pressure. To the obtained residue is added diethyl ether, 4 ml) and hexane (6 ml) to obtain the suspension of settled solids. The solid is filtered off, dried in the air flow and get listed in the title compound (46.6 mg, 11.7 per cent) in the form of a powder pale yellow color.

Range1H-NMR (CDCl3) δ (ppm): 3,35 (2H, Sirs), 5,19 (2H, m), 6,14 (1H, Sirs), 6,69 (1H, m), 7,30-7,52 (6H, m), 7,66 (1H, m), 7,83 (1H, m), of 7.97 (1H, m), 10,24 (1H, Sirs).

Example of getting 29-6

(3-Fluoro-4-{2-[3-methyl-3-(1-methylpiperidin-4-yl)ureido]pyridine-4-yloxy}phenyl)carbamino acid benzyl ester

After dissolving benzyl ester [4-(2-aminopyridine-4-yloxy)-3-forfinal]carbamino acid (41 mg) in N,N-dimethylformamide (2 ml) in an atmosphere of nitrogen was added triethylamine (0,0485 ml) and phenylcarbamate (0,0545 ml) with stirring in a bath containing ice water. The reaction mixture is brought to room temperature and the mixture is stirred for 30 minutes. To the reaction mixture is added methyl-(1-methylpiperidin-4-yl)amine (0,0675 ml) and stirred for 20 hours. The reaction mixture is distributed between ethyl acetate (30 ml) and saturated aqueous ammonium chloride (20 ml). The organic layer is separated and washed with saturated aqueous ammonium chloride (20 ml), water (20 ml) and saturated saline (20 ml) and dried over anhydrous sodium sulfate. The solvent is distilled off under reduced pressure and the resulting residue is purified column chromatography on silica gel (Fuji Silysia NH, eluent: heptane:e is ylacetic = 2:3-1:5). The fractions containing the target compound are concentrated under reduced pressure and get listed in the title compound (38,7 mg, 65,7%) as a colourless oil.

ESI-MS (neg.) (m/z): 506[M-H]-.

Connection example of getting 118 also can be synthesized in the following way.

Example of getting 118

4-(4-Benzyloxycarbonylamino-3-pertenece)pyridine-2-carboxylic acid

After suspension of ethyl 4-(4-benzyloxycarbonylamino-3-pertenece)pyridine-2-carboxylate (7.51 g) in ethanol (100 ml) and water (20 ml) at room temperature add lithium hydroxide (657 mg). The reaction mixture is stirred for 1 hour at room temperature. The reaction mixture was stirred while cooling in a bath with ice, and then add 1 N. hydrochloric acid (60 ml). After stirring for 5 minutes the reaction mixture was concentrated. After concentrating the precipitated crystals are filtered and washed with water. Then the crystals are dissolved in a mixture of ethyl acetate-tetrahydrofuran and the solution is dried over anhydrous sodium sulfate. The dried solution is concentrated under reduced pressure. The precipitate is suspended in hexane and filtered. The solid is dried, obtaining specified in the header connection (5,04 g, 72,0%) as a solid pale yellow color.

Example of getting 118-1

Ethyl 4-chloropyridin-2-carboxylat

A mixture of 4-chloropyridin-2-carboxylic acid (39,4 g) and thionyl chloride (64 ml) is heated and stirred for 6 hours at 100°C in nitrogen atmosphere. Then the reaction mixture is cooled to room temperature. After concentration under reduced pressure, the reaction mixture is subjected to azeotropic distillation with toluene. The residue is gradually added to the ethanol under stirring and cooling in a bath with ice. The reaction mixture is stirred for 25,5 hours at room temperature. Then the reaction mixture was concentrated under reduced pressure. To the residue is added saturated aqueous solution of sodium bicarbonate and the mixture extracted with ethyl acetate. The organic layer was washed with saturated saline and dried over anhydrous sodium sulfate. The dried organic layer is concentrated under reduced pressure, obtaining specified in the header connection (38,8 g, 83.6 percent) in the form of a brown oil.

Range1H-NMR (CDCl3) δ (ppm): of 1.46 (3H, t, J=7.2 Hz), 4,50 (2H, q, J=7.2 Hz), 7,49 (1H, DD, J=2.0 a, 5,2 Hz), 8,15 (1H, d, J=2.0 Hz), 8,67 (1H, d, J=5,2 Hz).

Example of getting 118-2

Ethyl 4-(3-fluoro-4-nitrophenoxy)pyridine-2-carboxylate

After adding 3-fluoro-4-NITROPHENOL (24,7 g) and chlorobenzene (7,0 ml) to ethyl 4-chloropyridin-2-carboxylate (19,4 g) the mixture is heated and stirred for 4 hours at 120°C in nitrogen atmosphere. Then reaction the second mixture is cooled to room temperature. Add ethyl acetate (400 ml) and saturated aqueous solution of sodium carbonate (400 ml) and the mixture is stirred for 27 hours at room temperature. The stirring is stopped and the aqueous layer was separated. To the organic layer again add saturated aqueous solution of sodium carbonate and the mixture is stirred at room temperature for 2 days. Stirring is again stopped and the aqueous layer was separated. The aqueous layer was extracted with ethyl acetate (300 ml). The organic layers are combined and washed with saturated saline solution. The organic layer is dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The residue is purified column chromatography on silica gel (eluent: heptane:ethyl acetate = 2:1 to 1:1, then ethyl acetate). The fractions containing the target compound, concentrate, and get mentioned in the title compound (12.9 g, 40.2 per cent) in the form of a brown oil.

Range1H-NMR (CDCl3) δ (ppm): 1,45 (3H, t, J=7.2 Hz), of 4.49 (2H, q, J=7.2 Hz), 6,97-7,01 (2H, m), 7,16 (1H, DD, J=2,4, 5,6 Hz), 7,79 (1H, d, J=2.4 Hz), to 8.20 (1H, m), 8,76 (1H, d, J=5.6 Hz).

ESI-MS (m/z): 329 [M+Na]+.

Example of getting 118-3

Ethyl 4-(4-benzyloxycarbonylamino-3-pertenece)pyridine-2-carboxylate

After adding 20% palladium hydroxide on coal (1.0 g) to a solution of ethyl 4-(3-fluoro-4-nitrophenoxy)pyridine-2-carboxylate (8,56 g) in ethanol (150 ml), the reaction mixture p is remediat for 9.5 hours at room temperature in a hydrogen atmosphere. Then the catalyst is filtered off. To the filtrate is added 4 n hydrochloric acid in ethyl acetate (14 ml) and the mixture concentrated. Concentrating stop before the mixture evaporates add dry. Add water (75 ml), acetone (150 ml) and sodium hydrogen carbonate (11.8 g). The mixture is then stirred while cooling in a bath with ice, and add benzyloxycarbonylamino (6,00 ml). The reaction mixture is stirred for 4 hours at room temperature. Then the reaction mixture was concentrated under reduced pressure. The residue is extracted with ethyl acetate. The organic layer was washed with saturated saline and dried over anhydrous sodium sulfate. Then the residue is concentrated under reduced pressure and purified column chromatography on silica gel (eluent: heptane:ethyl acetate = 1:1-1:2, then ethyl acetate). The fractions containing the target compound are concentrated under reduced pressure. The obtained solid is suspended in hexane. The suspension is left to stand for some time and remove supernatant with a pipette. The residue is dried, obtaining specified in the header connection (7.51 g, 65,4%) as a solid pale yellow color.

Range1H-NMR (CDCl3) δ (ppm): USD 1.43 (3H, m), 4,45-to 4.52 (2H, m), of 5.24 (2H, c), 6,87-6,92 (2H, m), of 6.99 (1H, DD, J=2,4, 5,6 Hz), 7,35-7,45 (6H, m), the 7.65 (1H, d, J=2.4 Hz), 8,19 (1H, m), at 8.60 (1H, d, J=5.6 Hz).

Connection use the and get 119-1 also can be synthesized in the following way.

Example of getting 119-1

Benzyl [4-(2-aminopyridine-4-yloxy)-2-forfinal]carbamate

4 n hydrochloric acid in ethyl acetate (120 ml) is cooled in a bath with ice. After adding with stirring tert-butyl [4-(4-benzyloxycarbonylamino-3-pertenece)pyridine-2-yl]carbamate (to 3.92 g), stirring is continued for 10 minutes in a bath with ice. Then the reaction mixture was stirred for 3.5 hours at room temperature. The reaction mixture was concentrated under reduced pressure. Then it is distributed between ethyl acetate (150 ml) and saturated aqueous sodium bicarbonate (70 ml). The aqueous layer was extracted with ethyl acetate (50 ml). The combined organic layer was washed with saturated saline and dried over anhydrous sodium sulfate. The dried organic layer is concentrated under reduced pressure. The resulting crystals are then suspended in a mixture of hexane-ethyl acetate (5:1). The crystals are filtered and washed with a mixture of hexane-ethyl acetate (5:1). They are then dried by suction at room temperature and get the specified header connection (with 2.93 g, 95.9 per cent) in the form of crystals of pale yellow color.

Example of getting 119-3

tert-Butyl [4-(4-benzyloxycarbonylamino-3-pertenece)pyridine-2-yl]carbamate

The triethylamine (4.6 ml) is added to a suspension of 4-(4-benzyloxycarbonylamino-3-pertenece)the feast of the DIN-2-carboxylic acid (5,04 g) in tert-butanol (50 ml) at room temperature and the mixture is stirred. After adding diphenylphosphinite (3,13 ml) at room temperature, the mixture is stirred for 30 minutes at room temperature in a nitrogen atmosphere. Then, it is heated and stirred at 90°C for 30 minutes and at 100°C for 4 hours. Then the reaction mixture is cooled to room temperature. Add ethyl acetate (25 ml) and the reaction mixture is stirred for 30 minutes, cooling in a bath with ice. The precipitated crystals are filtered and washed with diethyl ether. They are then dried in a stream of air for 1 hour at room temperature and get the specified header connection (to 3.92 g, 65,5%) as colorless crystals.

Range1H-NMR (DMSO-d6) δ (ppm): to 1.42 (9H, c)to 5.17 (2H, c), 6,62 (1H, DD, J=2,4, 5,6 Hz), 7,01 (1H, DD, J=2,2, 8,8 Hz), 7,21 (1H, DD, J=2,2, 11.2 Hz), 7,35-7,42 (6H, m), of 7.70 (1H, m)to 8.14 (1H, d, J=5.6 Hz), at 9.53 (1H, c), 9,83 (1H, c).

Example 167

4-(Azetidin-1-yl)piperidine-1-carboxylic acid {6-[2-fluoro-4-(3-phenylacetylamino)phenoxy]pyrimidine-4-yl}amide

After dissolving 4-(azetidin-1-yl)piperidine-1-carboxylic acid [6-(4-amino-2-pertenece)pyrimidine-4-yl]amide (40 mg) in ethanol (1 ml) under nitrogen atmosphere add D-10-camphorsulfonic acid (to 22.3 mg) and the mixture stirred for 5 minutes. Add phenylacetonitrile (34,1 mg) in acetonitrile (0.5 ml×3) and the mixture is stirred for 30 minutes. The reaction mixture distribution is Aut between ethyl acetate (30 ml) and saturated aqueous sodium hydrogen carbonate (20 ml), the organic layer was washed with saturated aqueous sodium hydrogen carbonate (20 ml), water (20 ml) and saturated saline (20 ml), then dried over anhydrous sodium sulfate. The solvent is distilled off under reduced pressure. The resulting residue is purified column chromatography on silica gel (Fuji Silysia NH, eluent: ethyl acetate) and then the fractions containing the target compound are concentrated under reduced pressure. To the obtained residue is added diethyl ether (1.5 ml) and hexane (1.5 ml) to give a suspension. The solid is filtered off, dried in a stream of air, which is specified in the header of the connection (of 33.5 mg, 61.8 percent) in the form of white powder.

Range1H-NMR (CDCl3) δ (ppm): 1,22 of 1.50 (2H, m), of 1.74 (2H, m)2,07 (2H, m), of 2.25 (1H, m), 3,11 (2H, m), 3,20 (4H, m), 3,74 (2H, c), with 3.89 (2H, m), 7,08-of 7.55 (8H, m), a 7.62 (1H, m), 7,86 (1H, DD, J=2,4, and 11.6 Hz), with 8.33 (1H, m)to 8.41 (1H, Sirs), 12,42 (1H, Sirs).

ESI-MS (m/z): 564[M+H]+.

Example of getting 167-1

The dihydrochloride 4-(azetidin-1-yl)-1-benzylpiperidine

The triethylamine (3,51 ml) are added to a suspension of the hydrochloride of azetidine (2.35 g) in tetrahydrofuran (60 ml). Add 1-benzyl-4-piperidone (3,71 ml) and acetic acid (2,29 ml) and the mixture is stirred in a bath with ice. Then add triacetoxyborohydride sodium (6,36 g) and dichloromethane (60 ml) and the mixture is stirred for a 3.3 hours at room temperature. After adding carbonate is the atrium before the termination of the foam to the reaction mixture are added water (50 ml), ethyl acetate (300 ml) and saturated saline (50 ml) and spend the mixture distribution. The aqueous layer was extracted with ethyl acetate (200 ml). The organic layers are combined and washed with saturated aqueous sodium bicarbonate and dried over anhydrous sodium sulfate. The dried organic layer is concentrated under reduced pressure, obtaining a pale brown oil. The oil is dissolved in a mixture of diethyl ether (20 ml) - hexane (20 ml) and added 4 n hydrochloric acid in ethyl acetate (11 ml). The precipitated solid is filtered and washed with hexane. The solid is dried in the air stream and receive untreated specified in the header connection (6,55 g, quantitative yield) as a solid white color.

ESI-MS (m/z): 231[M+H]+.

Example of getting 167-2

The dihydrochloride 4-(azetidin-1-yl)piperidine

After adding 10% palladium on coal (600 mg) to a solution of the crude dihydrochloride 4-(azetidin-1-yl)-1-benzylpiperidine (6,55 g) in a mixture of 2-propanol (50 ml) - water (50 ml) the mixture is stirred for 23 hours at room temperature in a hydrogen atmosphere. The catalyst is filtered off, washed with 2-propanol and then the filtrate is concentrated. The residue is suspended in a mixture of ethanol (10 ml) - hexane (50 ml). Then it is filtered off and washed with 10 ml of ethanol. The filter cake is dried in a stream of air is getting mentioned in the title compound (4.26 deaths / g) as white powder.

Range1H-NMR (CD3OD) δ (ppm): 1,70-1,80 (2H, m), of 2.25 (2H, m), 2.49 USD (2H, m), 2,86-of 3.12 (2H, m), 3,55 (2H, m), of 3.60 (1H, m), 4,22 (4H, m).

ESI-MS (m/z): 141[M+H]+.

Example of getting 167-3

4-(Azetidin-1-yl)piperidine-1-carboxylic acid [6-(2-fluoro-4-nitrophenoxy)pyrimidine-4-yl]amide

After adding triethylamine (0,278 ml) and phenylcarbamate (0,176 ml) to a solution of 6-(2-fluoro-4-nitrophenoxy)pyrimidine-4-ylamine (200 mg) in tetrahydrofuran (10 ml) at room temperature, the mixture is stirred for 15 minutes at room temperature. The reaction mixture is distributed between ethyl acetate (60 ml) and water (50 ml). The organic layer is dried over anhydrous magnesium sulfate and concentrated under reduced pressure. After adding to the residue N,N-dimethylformamide (3.0 ml), triethylamine (1.0 ml) dihydrochloride and 4-(azetidin-1-yl)piperidine (681 mg) the mixture is stirred for 10 hours at room temperature. The reaction mixture was partitioned between 1 N. aqueous sodium hydroxide solution (50 ml) and ethyl acetate (100 ml). The organic layer was washed with saturated saline and dried over anhydrous sodium sulfate. The dried organic layer is concentrated under reduced pressure. The residue is purified column chromatography on silica gel (Fuji Silysia NH, eluent: ethyl acetate, then ethyl acetate:methanol = 10:1). The fractions containing the target compound, concentrate, not getting the shelled specified in the title compound in the form of solid pale yellow color (364 mg).

ESI-MS (m/z): 417[M+H]+.

Example of getting 167-4

4-(Azetidin-1-yl)piperidine-1-carboxylic acid [6-(4-amino-2-pertenece)pyrimidine-4-yl]amide

After adding 10% palladium on coal (85 mg) to a solution of 4-(azetidin-1-yl)piperidine-1-carboxylic acid (6-(2-fluoro-4-nitrophenoxy)pyrimidine-4-yl)amide (364 mg) in methanol (20 ml) the mixture is stirred for 12 hours at room temperature in a hydrogen atmosphere. The catalyst is filtered off and the filtrate is concentrated under reduced pressure. The obtained solid is suspended in ethyl acetate and diluted with diethyl ether. The solid is filtered and washed with diethyl ether. Then it is dried in the air flow, getting mentioned in the title compound (160 mg) as white powder.

Range1H-NMR (DMSO-d6) δ (ppm): 1,09 (2H, m), of 1.57 (2H, m), 1,90 (2H, m)to 2.15 (1H, m), 3,05 (6H, m), with 3.79 (2H, m), 5,38 (2H, m), 6,37 (1H, DD, J=2,4, and 8.2 Hz), 6,46 (1H, DD, J=2,4, 13,2 Hz), 6,93 (1H, m), 7,22 (1H, d, J=1.0 Hz), of 8.37 (1H, d, J=1.0 Hz), 9,71 (1H, m).

ESI-MS (m/z): 387[M+H]+.

Example 168

4-(Azetidin-1-yl)piperidine-1-carboxylic acid {4-[3-fluoro-4-(3-phenylacetylamino)phenoxy]pyridine-2-yl}amide

After adding 10% palladium on coal (26,2 mg) to a solution of benzyl [4-(2-{[4-(azetidin-1-yl)piperidine-1-carbonyl]amino}pyridine-4-yloxy)-2-forfinal]carbamate (128 mg) in tetrahydrofuran (10 ml) the mixture is stirred for 16 hours at room temp is the temperature in hydrogen atmosphere. The catalyst is filtered off and washed with tetrahydrofuran (4 ml). A portion of the mixture by volume of 7 ml of concentrated almost to dryness. A solution of 2-phenylacetonitrile was 32.8 mg) in toluene (3.0 ml) are added to a solution of the residue in ethanol (3.0 ml) at room temperature and the mixture is stirred for 2 hours at room temperature. The reaction mixture is distributed between ethyl acetate (60 ml) and saturated aqueous sodium hydrogen carbonate (30 ml). The organic layer was washed with saturated saline and dried over anhydrous sodium sulfate. Then the organic layer is concentrated under reduced pressure. The residue is purified column chromatography on silica gel (Fuji Silysia NH, eluent: ethyl acetate, then ethyl acetate:methanol = 20:1). The fractions containing the target compound concentrate. The residue is purified by LC-MS. The fractions containing the target compound, concentrated and partitioned between saturated aqueous sodium bicarbonate and ethyl acetate. The organic layer is dried over anhydrous sodium sulfate and concentrated under reduced pressure. The obtained solid is suspended in hexane. The solid is filtered and washed with hexane. Then it is dried in the air stream, receiving specified in the header of the compound (8,9 mg, 12.9 percent) in the form of white powder.

Range1H-NMR (CD3OD) δ (ppm): 1,16 (2H, m, of 1.80 (2H, m), 2,11 (2H, m), is 2.37 (1H, m), 2.91 in (2H, m), 3,30 (4H, m), 3,76 (2H, c), 4.09 to (2H, m), only 6.64 (1H, DD, J=2,4, 6,0 Hz), 6,97 (1H, m), 7,05 (1H, DD, J=2,4, and 10.8 Hz), 7,26-to 7.35 (6H, m), 7,49 (1H, d, J=2,4 Hz), 8,11 (1H, d, J=6.0 Hz), of 8.27 (1H, m).

ESI-MS (m/z): 563[M+H]+, 585[M+Na]+.

Example of getting 168-1

Benzyl [4-(2-{[4-(azetidin-1-yl)piperidine-1-carbonyl]amino}pyridine-4-yloxy)-2-forfinal]carbamate

After adding triethylamine (0,0814 ml) and phenylcarbamate (0,0641 ml) to a solution of benzyl [4-(2-aminopyridine-4-yloxy)-2-forfinal]carbamate (103 mg) in tetrahydrofuran (5.0 ml) at room temperature, the mixture is stirred for 15 minutes at the same temperature. Then the reaction mixture is concentrated and to the residue is added N,N-dimethylformamide (3.0 ml), triethylamine (1.0 ml) and the dihydrochloride 4-(azetidin-1-yl)piperidine (249 mg) and the mixture is stirred for 10.5 hours at room temperature. The reaction mixture was partitioned between 1 N. aqueous sodium hydroxide solution (50 ml) and ethyl acetate (100 ml). The organic layer was washed with saturated saline and dried over anhydrous sodium sulfate. The dried organic layer is concentrated under reduced pressure. The residue is purified column chromatography on silica gel (Fuji Silysia NH, eluent: ethyl acetate, then ethyl acetate:methanol = 10:1). The fractions containing the target compound, concentrate, getting mentioned in the title compound (128 mg, 84.4 per cent) in the form of oil pale yellow is the first color.

Range1H-NMR (CDCl3) δ (ppm): 1.26 in (2H, m), 1.69 in (2H, m)to 2.06 (2H, m), 2,19 (1H, m), 3,01 (2H, m), 3,18 (4H, m), 3,90 (2H, m), with 5.22 (2H, c), of 6.50 (1H, DD, J=2,0, 5.8 Hz), at 6.84-6.89 in (3H, m), of 6.99 (1H, c), 7,33-7,41 (5H, m), a 7.62 (1H, d, J=2.0 Hz), 8,03 (1H, d, J=5.8 Hz), 8,11 (1H, m).

ESI-MS (m/z): 520 [M+H]+.

Example 169

4-Dimethylaminopyridine-1-carboxylic acid {4-[3-fluoro-4-(3-phenylacetylamino)phenoxy]pyridine-2-yl}amide

After adding 10% palladium on coal (21.2 mg) to a solution of benzyl (4-{2-[(4-dimethylaminopyridine-1-carbonyl)amino]pyridine-4-yloxy}-2-forfinal)carbamate (101 mg) in tetrahydrofuran (10 ml) the mixture is stirred for 16 hours at room temperature in a hydrogen atmosphere. The catalyst is filtered off and washed with tetrahydrofuran (4 ml)to give a solution of 4-dimethylaminopyridine-1-carboxylic acid [4-(4-amino-3-pertenece)pyridine-2-yl]amide in tetrahydrofuran (14 ml). A portion of the mixture by volume of 7 ml of concentrated almost to dryness. To a solution of the residue in ethanol (3.0 ml) add a solution of 2-phenylacetonitrile (26,4 mg) in toluene (3.0 ml) at room temperature and the mixture is stirred for 2 hours at the same temperature. The reaction mixture is distributed between ethyl acetate (60 ml) and saturated aqueous sodium hydrogen carbonate (30 ml). The organic layer was washed with saturated saline and dried over anhydrous sodium sulfate. Then the organic layer is concentrated when s is low pressure. The residue is purified column chromatography on silica gel (Fuji Silysia NH, eluent: ethyl acetate, then ethyl acetate:methanol = 20:1). The obtained solid is suspended in hexane and filtered. Then it is washed with hexane and purified by LC-MS (eluent: system acetonitrile-water-triperoxonane acid). The fractions containing the target compound, concentrated, then the residue partitioned between saturated aqueous sodium bicarbonate and ethyl acetate. The organic layer is dried over anhydrous sodium sulfate. Then the organic layer is concentrated and receiving specified in the header connection (8,4 mg) as white powder.

Range1H-NMR (CD3OD) δ (ppm): of 1.37 to 1.47 (2H, m), with 1.92 (2H, m), 2,31 (6H, c), 2,47 (1H, m), is 2.88 (2H, m), 3,76 (2H, c), 4,20 (2H, m), 6,40 (1H, DD, J=2,4, 6,0 Hz), 6,97 (1H, m),? 7.04 baby mortality (1H, DD, J=2,6, and 11.0 Hz), 7,26 and 7.36 (6H, m), 7,49 (1H, d, J=2.4 Hz), 8,11 (1H, d, J=6.0 Hz), of 8.27 (1H, m).

ESI-MS (m/z): 551 [M+H]+, 573 [M+Na]+.

Example of getting 169-1

The dihydrochloride of 4-dimethylamino-1-benzylpiperidine

After addition of 1-benzyl-4-piperidone (20 ml) and acetic acid (6,15 ml) to a suspension of dimethylamine hydrochloride (11,0 g) in dichloroethane (300 ml), the mixture is stirred in a bath with ice. Add triacetoxyborohydride sodium (34.3 g), and after stirring in a bath with ice for 20 minutes the mixture is stirred for a further 5.5 hours at room temperature. Then to reactio the Noah mixture is added water (200 ml). Then add sodium carbonate until the aqueous layer becomes slightly alkaline, and the mixture is stirred for 10 minutes at room temperature. Then distribute the mixture and the aqueous layer was extracted with ethyl acetate. The combined organic layer is dried over anhydrous sodium sulfate. The dried organic layer is concentrated under reduced pressure. To the residue is added diethyl ether (100 ml) and 4 n hydrochloric acid in ethyl acetate (59,5 ml). The resulting mixture was diluted with diethyl ether (50 ml) and hexane (50 ml), after which the solid is filtered off. The filtered solid is washed with diethyl ether. Then it is dried in the air stream, receiving untreated specified in the title compound (30.0 g) in the form of a solid pale brown color.

ESI-MS (m/z): 219[M+H]+.

Example of getting 169-2

The dihydrochloride of 4-dimethylaminopyridine

After adding 10% palladium on coal (2.0 g) to a solution of the crude dihydrochloride 4-dimethylamino-1-benzylpiperidine (30.0 g) in a mixture of 2-propanol (300 ml) - water (300 ml), the mixture is stirred for 22 hours at room temperature in a hydrogen atmosphere. The catalyst is filtered off and washed with 2-propanol. The filtrate is concentrated. The obtained crystals suspended in ethanol (50 ml). They are then diluted with diethyl ether (50 ml). Then kr is the growth filtered and washed with methanol (10 ml). They are then dried in a stream of air, getting mentioned in the title compound (16.4 g) as colorless crystals.

Range1H-NMR (CD3OD) δ (ppm): 1,94-of 2.05 (2H, m), 2,35 (2H, m), 2,89 (6H, c), 3,06-and 3.16 (2H, m), 3,52-3,62 (3H, m).

Example of getting 169-3

Benzyl (4-{2-[(4-dimethylaminopyridine-1-carbonyl)amino]pyridine-4-yloxy}-2-forfinal)carbamate

After adding triethylamine (0,0814 ml) and phenylcarbamate (0,0641 ml) to a solution of benzyl[4-(2-aminopyridine-4-yloxy)-2-forfinal]carbamate (103 mg) in tetrahydrofuran (5.0 ml) at room temperature, the mixture is stirred for 15 minutes at the same temperature. The reaction mixture was concentrated under reduced pressure and add N,N-dimethylformamide (3.0 ml), triethylamine (1.0 ml) and the dihydrochloride of 4-dimethylaminopyridine (235 mg), after which the mixture was stirred at room temperature. The reaction mixture was partitioned between 1 N. aqueous sodium hydroxide solution (50 ml) and ethyl acetate (100 ml). The organic layer was washed with saturated saline and dried over anhydrous sodium sulfate. Then the organic layer is concentrated under reduced pressure. The residue is purified column chromatography on silica gel (Fuji Silysia NH, eluent: ethyl acetate, then ethyl acetate:methanol = 10:1). The fractions containing the target compound, concentrate, and get mentioned in the title compound (101 mg, 68.1 per cent) in the form of oil nl is the bottom-yellow color.

Range1H-NMR (CDCl3) δ (ppm): 1,27-of 1.55 (2H, m)to 1.86 (2H, m), and 2.27 (6H, c), of 2.34 (1H, m), 2,87 (2H, m), 4.09 to to 4.15 (2H, m), with 5.22 (2H, c), 6,51 (1H, DD, J=2,0, 5.6 Hz), 6,85-6,93 (3H, m), 7,06 (1H, Sirs), 7,33-7,41 (4H, m), 7,51 (1H, Sirs), 7,63 (1H, d, J=2.0 Hz), 8,03 (1H, d, J=5.6 Hz), 8,11 (1H, m).

ESI-MS (m/z): 508[M+H]+, 530[M+Na]+.

Example 170

3-[6-(2-Fluoro-4-{3-[2-(4-forfinal)acetyl]touraid}phenoxy)pyrimidine-4-yl]-1-methyl-1-(1-methylpiperidin-4-yl)urea

After dissolving 3-[6-(4-amino-2-pertenece)pyrimidine-4-yl]-1-methyl-1-(1-methylpiperidin-4-yl)urea (70,3 mg) in ethanol (2 ml) under nitrogen atmosphere add D-10-camphorsulfonic acid (43,7 mg) and the mixture stirred for 5 minutes. Add 0,24M solution of 2-(4-forfinal)acetylsalicylate in toluene (1,02 ml) and the mixture is stirred for 17.5 hours. Then to the reaction mixture add another portion 0,24M solution of 2-(4-forfinal)acetylsalicylate in toluene (0.3 ml) and stirring continued for 30 minutes. The reaction mixture is distributed between ethyl acetate (30 ml) and saturated aqueous sodium hydrogen carbonate (20 ml). The organic layer was washed with saturated aqueous sodium hydrogen carbonate (20 ml), water (20 ml) and saturated saline (20 ml), then dried over anhydrous sodium sulfate. The solvent is distilled off under reduced pressure. The resulting residue is purified column chromatography on silica gel (Fuji Silysia NH, eluent: heptane:e is ylacetic = 1:8) and then faction, containing the target compound are concentrated under reduced pressure. To the obtained residue is added diethyl ether (1 ml) and hexane (2 ml) and receive a suspension. The solid is filtered off, dried in a stream of air, which is specified in the header connection (to 39.4 mg, 36.8 percent) in the form of a powder pale yellow color.

Range1H-NMR (CDCl3) δ (ppm): 1,50-of 1.73 (2H, m), is 1.81 (2H, m), 2,12 (2H, m), 2,31 (3H, c), with 2.93 (3H, c), 2,96 (2H, m), and 3.72 (2H, c), 4,20 (1H, m), 7,13 (2H, m), 7,17-7,42 (5H, m), 7,69 (1H, m), 7,87 (1H, DD, J=2,8, the 11.6 Hz), 8,35 (1H, m), 8,48 (1H, Sirs), KZT 12.39 (1H, Sirs).

ESI-MS (m/z): 570[M+H]+.

Example 171

4-Dimethylaminopyridine-1-carboxylic acid [6-(2-fluoro-4-{3-[2-(4-forfinal)acetyl]touraid}phenoxy)pyrimidine-4-yl]amide

After dissolving 4-dimethylaminopyridine-1-carboxylic acid [6-(4-amino-2-pertenece)pyrimidine-4-yl]amide of them (89.3 mg) in ethanol (2 ml) add D-10-camphorsulfonic acid (55,3 mg) and stirred for 5 minutes under nitrogen atmosphere. Then add 0,24M solution of 2-(4-forfinal)acetylsalicylate in toluene (0.4 ml) and stirred for 1 hour. To the reaction mixture add another portion 0,24M solution of 2-(4-forfinal)acetylsalicylate in toluene (0.4 ml) and stirring is continued for 1 hour. The reaction mixture is distributed between ethyl acetate (30 ml) and saturated aqueous sodium hydrogen carbonate (20 ml), after which the organic layer is washed us is placed in an aqueous solution of sodium hydrogen carbonate (20 ml), water (20 ml), saturated brine (20 ml) and dried over anhydrous sodium sulfate. The solvent is distilled off under reduced pressure. The resulting residue is purified column chromatography on silica gel (Fuji Silysia NH, eluent: heptane:ethyl acetate = 8:1) and then the fractions containing the target compound are concentrated under reduced pressure. To the obtained residue is added diethyl ether (0.5 ml) and hexane (4.0 ml) to give a suspension. The solid is filtered off, dried in a stream of air, which is specified in the header connection (24,9 mg, 18,4%) as a solid white color.

Range1H-NMR (CDCl3) δ (ppm): 1,50 (2H, m), at 1.91 (2H, m), is 2.30 (6H, c), of 2.38 (1H, m), 2,96 (2H, m), 3,71 (2H, Sirs), of 4.12 (2H, m), 7,12 (2H, m), 7,16-to 7.50 (5H, m), 7,63 (1H, c), 7,86 (1H, m), with 8.33 (1H, c), 8,46 (1H, Sirs), 12,38 (1H, Sirs).

ESI-MS (m/z): 570[M+H]+.

Example 172

4-(Azetidin-1-yl)piperidine-1-carboxylic acid [6-(2-fluoro-4-{3-[2-(4-forfinal)acetyl]touraid}phenoxy)pyrimidine-4-yl]amide

After adding potassium thiocyanate (65,3 mg) and acetonitrile (4 ml) to 2-(4-forfinal)acetylchloride (58 mg) in a nitrogen atmosphere, the mixture is stirred for 2 hours at 60°C. the Reaction mixture is cooled to room temperature, then add ethyl acetate (30 ml) and saturated aqueous sodium hydrogen carbonate solution (20 ml) and stirring continued for 30 minutes. After distribution of the reaction mixture of the organic layer is separated and washed with saturated aqueous sodium hydrogen carbonate (20 ml), water (20 ml) and saturated saline (20 ml), after it is dried over anhydrous sodium sulfate. The solvent is distilled off under reduced pressure, obtaining the crude 2-(4-forfinal)acetylisoniazid in the form of a yellow oil. After dissolving 4-(azetidin-1-yl)piperidine-1-carboxylic acid [6-(4-amino-2-pertenece)pyrimidine-4-yl]amide (70 mg) in ethanol (2 ml) add D-10-camphorsulfonic acid (43 mg) and the mixture stirred for 5 minutes under nitrogen atmosphere. Then add 2-(4-forfinal)acetilsalicilic-acetonitrile (0.5 ml×3) and the mixture is stirred for 2 hours. The reaction mixture is distributed between ethyl acetate (30 ml) and saturated aqueous sodium hydrogen carbonate (20 ml) and the organic layer was washed with saturated aqueous sodium hydrogen carbonate (20 ml), water (20 ml) and saturated saline (20 ml), then dried over anhydrous sodium sulfate. The filtrate is concentrated under reduced pressure. The resulting residue is purified column chromatography on silica gel (Fuji Silysia NH, eluent: heptane:ethyl acetate = 1:5) and then the fractions containing the target compound are concentrated under reduced pressure. To the obtained residue is added diethyl ether (0.5 ml) and hexane (4 ml) to obtain the suspension of solids. The solid is filtered off, dried in a stream of air, which is specified in the connection (36,9 mg, 37,8%) as white powder.

Range1H-NMR (CDCl3) δ (ppm): 1,23-of 1.40 (2H, m), 1,63-of 1.84 (2H, m)2,07 (2H, m), of 2.25 (1H, m), 3,11 (2H, m), 3,20 (4H, m), 3,71 (2H, c), of 3.80-4.00 points (2H, m), 7,12 (2H, m), 7,18 is 7.50 (5H, m), a 7.62 (1H, c), 7,86 (1H, DD, J=2,4, and 11.6 Hz), with 8.33 (1H, c), 8,49 (1H, Sirs), 12,38 (1H, Sirs).

ESI-MS (m/z): 582[M+H]+.

Example 173

4-(Pyrrolidin-1-yl)piperidine-1-carboxylic acid [6-(2-fluoro-4-{3-[2-(4-forfinal)acetyl]touraid}phenoxy)pyrimidine-4-yl]amide

After adding potassium thiocyanate (388 mg) and acetonitrile (20 ml) to (4-forfinal)acetylchloride (345 mg) in a nitrogen atmosphere, the mixture is stirred for 2 hours at 60°C. the Reaction mixture is cooled to room temperature, then concentrated under reduced pressure, the obtained residue is added toluene (10 ml) and saturated aqueous sodium hydrogen carbonate solution (10 ml) and the mixture is stirred for 20 minutes, getting 0,2M solution of 2-(4-forfinal)acetylsalicylate in toluene.

After suspension of the crude 4-(pyrrolidin-1-yl)piperidine-1-carboxylic acid [6-(4-amino-2-pertenece)pyrimidine-4-yl]amide (88,4 mg) in ethanol (3 ml) add D-10-camphorsulfonic acid (51.3 mg) and the mixture stirred for 5 minutes. Add 0,2M solution of 2-(4-forfinal)acetylsalicylate in toluene (1.3 ml) and the mixture is stirred for 62 hours. The reaction mixture is distributed between ethyl acetate (30 ml) and saturated aqueous solution of hydrocar is onata sodium (20 ml), then the organic layer was washed with saturated aqueous sodium hydrogen carbonate (20 ml), water (20 ml) and saturated saline (20 ml) and dried over anhydrous sodium sulfate. The solvent is distilled off under reduced pressure and then the resulting residue is purified column chromatography on silica gel (Fuji Silysia NH, eluent: heptane:ethyl acetate = 1:9). The fractions containing the target compound, concentrate, and to the obtained residue is added diethyl ether (1 ml) and hexane (1.5 ml) to give a suspension. The solid is filtered off, dried in a stream of air, which is specified in the header connection (to 44.7 mg, 34%) as a powder pale pink color.

Range1H-NMR (CDCl3) δ (ppm): 1,27 (2H, m), is 1.81 (4H, m)of 1.97 (2H, m), 2,24 (1H, m), 2,59 (4H, m), 3.04 from (2H, m), 3,71 (2H, Sirs), a 4.03 (2H, m), 7,12 (2H, m), 7.18 in-to 7.32 (3H, m), 7,33-7,46 (2H, m), 7,63 (1H, m), 7,86 (1H, DD, J=2,4, and 11.6 Hz), with 8.33 (1H, m), 8,48 (1H, Sirs), 12,38 (1H, Sirs).

ESI-MS (m/z): 596[M+H]+.

Example of getting 173-1

4-(Pyrrolidin-1-yl)piperidine-1-carboxylic acid [6-(4-amino-2-pertenece)pyrimidine-4-yl]amide

After dissolving 6-(2-fluoro-4-nitrophenoxy)pyrimidine-4-ylamine (150 mg) in tetrahydrofuran (6 ml) in an atmosphere of nitrogen was added triethylamine (0,251 ml) and phenylcarbamate (0,226 ml), cooling in a bath containing ice water. The reaction mixture is brought to room temperature, stirred for 30 minutes and then the con is intronaut under reduced pressure. Once added to the obtained residue, 4-(pyrrolidin-1-yl)piperidine (370 mg) in N,N-dimethylformamide (6 ml) and the mixture is stirred for a 15.5 hours. The reaction mixture is distributed between ethyl acetate (30 ml) and saturated aqueous ammonium chloride (20 ml). The organic layer was washed with saturated aqueous ammonium chloride (20 ml), water (20 ml) and saturated saline (20 ml), then dried over anhydrous sodium sulfate. The solvent is distilled off under reduced pressure, after which the resulting residue is purified column chromatography on silica gel (Fuji Silysia NH, eluent: heptane:ethyl acetate = 1:5). The fractions containing the target compound are concentrated under reduced pressure and get the crude 4-(pyrrolidin-1-yl)piperidine-1-carboxylic acid [6-(2-fluoro-4-nitrophenoxy)pyrimidine-4-yl]amide (88,4 mg) in the form of oil pale yellow color.

After dissolving the crude product (88,4 mg) in methanol (6 ml) and tetrahydrofuran (6 ml) is added 10% palladium on coal (128 mg) in a nitrogen atmosphere. The atmosphere in the reaction vessel is replaced by hydrogen and the reaction mixture is stirred for 3 hours, after which the atmosphere in the reaction vessel is replaced by nitrogen. The catalyst is filtered off, washed with ethanol and the filtrate concentrated under reduced pressure. The resulting residue is purified column chromatography on silicagel is (Fuji Silysia NH, eluent: ethyl acetate:ethanol = 19:1), then the fractions containing the target compound are concentrated under reduced pressure and get the crude specified in the header connection (to 88.4 mg) as a yellow oil.

ESI-MS (m/z): 401[M+H]+.

Example 174

4-(Pyrrolidin-1-yl)piperidine-1-carboxylic acid [4-(2-fluoro-4-{3-[2-(4-forfinal)acetyl]ureido}phenoxy)pyridine-2-yl]amide

1,2-Dichloroethane (20 ml) are added to 2-(4-forfinal)ndimethylacetamide (282 mg) at room temperature under nitrogen atmosphere. The reaction mixture is heated to 110°C with stirring, then the reaction mixture add oxalicacid (0,201 ml) and stirred for 14,5 hours. The reaction mixture is cooled to room temperature and then concentrated under reduced pressure.

Once added to the obtained residue, N,N-dimethylformamide (4.5 ml) in an atmosphere of nitrogen was added 4-(pyrrolidin-1-yl)piperidine-1-carboxylic acid [4-(4-amino-2-pertenece)pyridine-2-yl]amide (245 mg) in N,N-dimethylformamide (0.5 ml×3) and the mixture is stirred for 1.5 hours. The reaction mixture is distributed between ethyl acetate (200 ml) and saturated aqueous sodium hydrogen carbonate (50 ml). The organic layer is separated and washed with saturated aqueous sodium hydrogen carbonate (50 ml), water (50 ml) and saturated saline (100 ml) in that order, then dried over anhydrous is a Ulfat sodium. The solvent is distilled off under reduced pressure, and the resulting residue is purified column chromatography on silica gel (Fuji Silysia NH, eluent: heptane:ethyl acetate = 1:5-1:8). The fractions containing the target compound are concentrated under reduced pressure, and then to the obtained residue is added diethyl ether (3.0 ml) and hexane (3.0 ml) to obtain the suspension of solids. The solid is filtered and then dried in the air stream, receiving specified in the header connection (171,2 mg, 48,3%) as white powder.

Range1H-NMR (CDCl3) δ (ppm): 1,44-of 1.66 (2H, m)to 1.79 (4H, m)of 1.93 (2H, m), of 2.20 (1H, m), 2.57 m (4H, m), 2,96 (2H, m), and 3.72 (2H, c)to 4.01 (2H, m), 6,23 (1H, DD, J=2,4, 5,6 Hz), 7,02-7,40 (4H, m), 7,21-7,34 (3H, m), 7,55-7,66 (2H, m), 7,94-8,13 (2H, m), 10,55 (1H, Sirs).

ESI-MS (m/z): 579[M+H]+.

Example 175

3-[6-(3-Fluoro-4-{3-[2-(4-forfinal)acetyl]touraid}phenoxy)pyrimidine-4-yl]-1-methyl-1-(1-methylpiperidin-4-yl)urea

Benzyl N-(2-fluoro-4-{6-[3-methyl-3-(1-methylpiperidin-4-yl)ureido]pyrimidine-4-yloxy}phenyl)carbamate (189 mg) was dissolved in tetrahydrofuran (20 ml). After adding 20% palladium hydroxide on coal (104 mg) the mixture is stirred for 10 hours in an atmosphere of hydrogen. The catalyst is filtered off and washed with ethyl acetate. The filtrate and washings are combined and concentrated under reduced pressure, obtaining the crude 3-[6-(4-amino-3-pertenece)pyrimidine-4-yl]-1-methyl-1-(1-methylpiperidin-4-yl)much the guilt in the form of a colourless oil [ESI-MS(m/z): 375[M+H] +].

After you have added at room temperature solution of 2-(4-forfinal)acetylsalicylate in toluene (0,2M, 3.4 ml) to a solution of crude 3-[6-(4-amino-3-pertenece)pyrimidine-4-yl]-1-methyl-1-(1-methylpiperidin-4-yl)urea and (+)-10-camphorsulfonic acid (86,2 mg) in ethanol (2.5 ml) the mixture is stirred for 4 hours. Then the reaction mixture is distributed between ethyl acetate and saturated aqueous sodium bicarbonate. The organic layer was washed with saturated aqueous sodium bicarbonate and saturated saline in this order, then dried over anhydrous sodium sulfate. The solvent is distilled off and the residue is purified column chromatography on silica gel (Fuji Silysia NH, eluent: ethyl acetate). The fractions containing the target compound are concentrated under reduced pressure and to the residue is added diethyl ether (2.0 ml)to precipitate crystals. The crystals are filtered and dried in a stream of air, getting mentioned in the title compound (21,0 mg, 10%) as white crystals.

Range1H-NMR (CDCl3) δ (ppm): 1,64-1,72 (2H, m), 1,74-of 1.88 (2H, m), 2,04-of 2.16 (2H, m), 2,31 (3H, c), 2,86 are 2.98 (5H, m), and 3.72 (2H, c), 4,18 (1H, m), 6,95-7,05 (2H, m), 7,09-to 7.15 (2H, m), 7,20-7,40 (3H, m), a 7.62 (1H, d, J=0.8 Hz), 8,35-8,42 (2H, m), 8,48 (1H, Sirs), 12,32 (1H, Sirs).

Example of getting 175-1

4-Chloro-6-(3-fluoro-4-nitrophenoxy)pyrimidine

After dissolving 2,6-dichlo the pyrimidine (5.0 g) and 3-fluoro-4-NITROPHENOL (6.11 g) in 1-methyl-2-pyrrolidinone (25 ml) at room temperature under nitrogen atmosphere add diisopropylethylamine (for 6.81 ml) and the mixture is stirred for 13 hours at 50° C. the Reaction mixture is cooled to room temperature and distributed between ethyl acetate and water. The organic layer is separated and washed with water, 1 N. aqueous sodium hydroxide solution, water, 10% aqueous solution of potassium hydrosulfate and saturated saline in this order, then dried over anhydrous sodium sulfate. The solvent is distilled off under reduced pressure, then the residue is added ethyl acetate (25 ml)to precipitate crystals. The crystals are filtered and dried in a stream of air, getting mentioned in the title compound (2,61 g, 30%) as white crystals. The filtrate is concentrated under reduced pressure, then to the obtained residue is added diethyl ether (30 ml) and the mixture is stirred. The precipitated crystals are filtered, washed with diethyl ether (5 MLH) and dried in a stream of air, getting mentioned in the title compound (3.98 g, 44%) as white crystals.

Range1H-NMR (CDCl3) δ (ppm): to 7.09 (1H, c), 7,14 (1H, m), 7,20 (1H, m), to 8.20 (1H, DD, J=8,8, 8,8 Hz), to 8.62 (1H, c).

Example of getting 175-2

4-(4-Amino-3-pertenece)-6-chloropyrimidine

After dissolving 4-chloro-6-(3-fluoro-4-nitrophenoxy)pyrimidine (9,726 g) in a mixture of ethanol (100 ml) - N,N-dimethylformamide (100 ml) at room temperature, add water (50 ml), ammonium chloride (20 g) and electrolytic iron powder (10 g), after which the MCA is ü stirred for 1 hour at 100° C. the Reaction mixture is cooled to room temperature. Before washing the ethyl acetate insoluble substances are removed using celite. The filtrate is concentrated under reduced pressure and then the residue is distributed between ethyl acetate and water. The organic layer was separated, washed with water and saturated saline solution in that order and dried over anhydrous sodium sulfate. The solvent is distilled off and the residue is dried under reduced pressure, obtaining specified in the header connection (8,204 g, 95%) as crystals pale yellow color.

Range1H-NMR (CDCl3) δ (ppm): 3,76 (2H, W), 6,74-of 6.90 (4H, m), at 8.60 (1H, c).

Example of getting 175-3

4-Amino-6-(4-amino-3-pertenece)pyrimidine

After dissolving 4-(4-amino-3-pertenece)-6-chloropyrimidine (2.25 g) in tetrahydrofuran (25 ml) and 7 N. solution of ammonia in methanol (50 ml) the mixture is heated in a sealed tube for 3 days at 130°C. the Reaction mixture is cooled to room temperature and distributed between ethyl acetate and 1 N. aqueous sodium hydroxide solution. The organic layer is separated and washed with saturated saline solution. Then the aqueous layer was re-extracted with ethyl acetate. The combined organic layer is dried over anhydrous sodium sulfate. The solvent is distilled off and the residue is purified column chromatography on silica gel (eluent: hepta is:ethyl acetate = 1:3, then ethyl acetate), obtaining mentioned in the title compound (0.73 g, 35%) as a purple solid.

Range1H-NMR (CDCl3) δ (ppm): at 3.69 (2H, W), to 4.81 (2H, W), 5,80 (1H, c), 6,70-6,86 (3H, m), 8,29 (1H, c).

Example of getting 175-4

Benzyl N-[4-(6-aminopyrimidine-4-yloxy)-2-forfinal]carbamate

After dissolving 4-amino-6-(4-amino-3-pertenece)pyrimidine (730 mg) in a mixture of acetone (60 ml) - water (30 ml) is added sodium hydrogen carbonate (335 mg) and benzylchloride (0,550 ml), cooling in a bath containing ice water, whereupon the mixture is stirred at the same temperature. After 3.5 hours added sodium hydrogen carbonate (140 mg) and benzylchloride (0,120 ml) and stirring is continued for 1 hour. The reaction mixture was concentrated under reduced pressure, to the residue is added ethyl acetate (50 ml) - tetrahydrofuran (100 ml) and saturated aqueous sodium hydrogen carbonate solution (50 ml), after which the mixture is stirred. The organic layer is separated, washed with a small amount of saturated salt solution and then concentrated under reduced pressure. To the residue is added ethyl acetate (25 ml) and the mixture is stirred. Precipitated insoluble fraction is filtered before washing with ethyl acetate (5 ml×3). The filtrate is concentrated under reduced pressure and the resulting residue is purified column chromatography on silica gel (eluent: hepta is:ethyl acetate = 1:2 to 1:4), getting listed in the title compound (514 mg, 44%) as a powder pale brown color.

Range1H-NMR (CDCl3) δ (ppm): a 4.86 (2H, Sirs), 5,23 (2H, c), 5,86 (1H, d, J=0.8 Hz), 6,86 (1H, Sirs), 6,90-to 6.95 (2H, m), 7,30 was 7.45 (5H, m), 8,13 (1H, m), of 8.28 (1H, c).

Example of getting 175-5

Benzyl N-(2-fluoro-4-{6-[3-methyl-3-(1-methylpiperidin-4-yl)ureido]pyrimidine-4-yloxy}phenyl)carbamate

After adding a solution of 1-methyl-4-methylaminopropane (0,355 ml) in N,N-dimethylformamide (2.5 ml) to the crude phenyl N-[6-(4-benzyloxycarbonylamino-3-pertenece)pyrimidine-4-yl]-N-(phenoxycarbonyl)carbamate (358 mg) at room temperature, the mixture is stirred for 2 hours. The reaction mixture is distributed between ethyl acetate and water. The organic layer is separated and washed with 1 N. aqueous sodium hydroxide solution and saturated saline solution in that order and then dried over anhydrous sodium sulfate. The solvent is distilled off and the residue is purified column chromatography on silica gel (Fuji Silysia NH, eluent: ethyl acetate, then ethyl acetate:methanol = 95:5), receiving specified in the header connection (189,4 mg) as white powder.

Range1H-NMR (CDCl3) δ (ppm): 1.60-to 1,90 (4H, m), 2,04 with 2.14 (2H, m), is 2.30 (3H, c), 2,80-3,00 (5H, m), 4,18 (1H, m), 5,23 (2H, c), to 6.88 (1H, m), 6,92-of 6.96 (2H, m), 7,29 (1H, Sirs), 7,30 was 7.45 (5H, m), 7,58 (1H, c), 8,16 (1H, m), scored 8.38 (1H, c).

Example 176

4-(Pyrrolidin-1-yl)piperidine-1-carboxylic acid [4-(3-f the PR-4-{3-[2-(4-forfinal)acetyl]touraid}phenoxy)pyridine-2-yl]amide

After adding 20% palladium hydroxide on coal (up 40.7 mg) to a solution of benzyl [2-fluoro-4-(2-{[4-(pyrrolidin-1-yl)piperidine-1-carbonyl]amino}pyridine-4-yloxy)phenyl]carbamate (155 mg) in tetrahydrofuran (10 ml) the mixture is stirred for 13 hours at room temperature in a hydrogen atmosphere. Then to the reaction mixture are added 20% palladium hydroxide on the corner (of 81.4 mg) and stirring is continued for 3.5 hours at room temperature in a hydrogen atmosphere. The catalyst is filtered off and washed with tetrahydrofuran, receiving a solution of 4-(pyrrolidin-1-yl)piperidine-1-carboxylic acid [4-(4-amino-3-pertenece)pyridine-2-yl]amide in tetrahydrofuran (22 ml) (ESI-MS (m/z: 400 [M+H]+). To portions of the resulting solution with a volume of 11 ml add ethanol (4.0 ml) and (1S)-(+)-10-camphorsulfonic acid (67,4 mg) and the mixture stirred for 5 minutes at room temperature. Then at room temperature add 0,2M solution of 2-(4-forfinal)acetylsalicylate in toluene (0,870 ml) and the mixture is stirred at room temperature for 1 hour. Again add 0,2M solution of 2-(4-forfinal)acetylsalicylate in toluene (0,400 ml) and the mixture is stirred at room temperature for 2 hours. Add another portion 0,2M solution of 2-(4-forfinal)acetylsalicylate in toluene (0,400 ml) and the mixture is stirred at room temperature for 2 hours. Add ceremnoy portion 0,2M solution of 2-(4-forfinal)acetylsalicylate in toluene (0,700 ml) and the mixture is stirred at room temperature for 45 minutes. The reaction mixture was partitioned between saturated aqueous sodium bicarbonate and ethyl acetate. The organic layer was washed with saturated saline and dried over anhydrous sodium sulfate. It is then concentrated under reduced pressure and purified column chromatography on silica gel (Fuji Silysia NH, eluent: heptane:ethyl acetate = 1:1 to 1:2, then ethyl acetate). The fractions containing the target compound are concentrated under reduced pressure. The residue is purified by LC-MS (eluent: based on a mixture of water-acetonitrile with the addition of triperoxonane acid). The fractions containing the target compound, concentrate, immediately thereafter dried under reduced pressure and partitioned between saturated aqueous sodium bicarbonate and ethyl acetate. The organic layer was washed with saturated saline and then dried over anhydrous sodium sulfate. The organic layer is concentrated under reduced pressure, obtaining the crude target compound (24.5 mg, 28.4 per cent). To it add a mixture of diethyl ether:heptane = 1:1 to obtain a solid substance. The solid is suspended, filtered and the crystals washed with hexane. Then the crystals are dried in a stream of air, getting mentioned in the title compound (15,4 mg) as white powder.

Range1H-NMR (CDCl3) δ (ppm): 1,48 is 1.58 (2H, m), of 1.80 (4H, m), 1,4 (2H, m), 2,22 (1H, m), 2,58 (4H, m), 2,98 (2H, m), and 3.72 (2H, c), was 4.02 (2H, m), 6,56 (1H, DD, J=2,4, 6,0 Hz)6,91 (2H, d, J=8,8 Hz), 7,09-7,14 (2H, m), 7,25-to 7.32 (3H, m), 7,68 (1H, d, J=2.4 Hz), 8,08 (2H, d, J=6.0 Hz), 8,32 (1H, m), 12,30 (1H, Sirs).

ESI-MS (m/z): 595[M+H]+.

Example 177

4-(Azetidin-1-yl)piperidine-1-carboxylic acid [4-(3-fluoro-4-{3-[2-(4-forfinal)acetyl]touraid}phenoxy)pyridine-2-yl]amide

After adding 10% palladium on coal (26,2 mg) to a solution of benzyl [4-(2-{[4-(azetidin-1-yl)piperidine-1-carbonyl]amino}pyridine-4-yloxy)-2-forfinal]carbamate (128 mg) in tetrahydrofuran (10 ml) the mixture is stirred for 16 hours at room temperature in a hydrogen atmosphere. The catalyst is filtered off and washed with tetrahydrofuran (4 ml)to give a solution of 4-(azetidin-1-yl)piperidine-1-carboxylic acid [4-(4-amino-3-pertenece)pyridine-2-yl]amide in tetrahydrofuran (approximately 14 ml) (ESI-MS (m/z): 386[M+H]+). The resulting solution was concentrated under reduced pressure to 4.5 ml and to a portion of the concentrate volume of 1.5 ml add ethanol (1.0 ml) and (1S)-(+)-10-camphorsulfonic acid (36,4 mg), after which the mixture is stirred for 5 minutes at room temperature. Add 0,2M solution of 2-(4-forfinal)acetylsalicylate in toluene (0,588 ml) and the mixture is stirred at room temperature for 2 hours. The reaction mixture was partitioned between saturated aqueous sodium bicarbonate and ethyl acetate. The organic layer is dried over anhydrous sodium sulfate. It is then concentrated under reduced pressure and purified column chromatography on silica gel (Fuji Silysia NH, eluent: heptane:ethyl acetate = 1:2, then ethyl acetate). The fractions containing the target compound are concentrated under reduced pressure. The residue is purified by LC-MS (eluent: based on a mixture of water-acetonitrile with the addition of triperoxonane acid). The fractions containing the target compound, concentrated and then partitioned between saturated aqueous sodium bicarbonate and ethyl acetate. The organic layer was washed with saturated saline and then dried over anhydrous sodium sulfate. The organic layer is concentrated under reduced pressure, obtaining the crude target compound (15,5 mg). The crude product utverjdayut, adding hexane (1 ml). The obtained solid is suspended, filtered and then washed with hexane. Then it is dried in the air flow, getting mentioned in the title compound (11.0 mg) as white powder.

Range1H-NMR (CDCl3) δ (ppm): of 1.23 to 1.47 (2H, m), of 1.74 (2H, m), of 2.08 (2H, m), and 2.26 (1H, m), 3.04 from (2H, m), 3,24 (4H, m), and 3.72 (2H, c)to 3.92 (2H, m), 6,55 (1H, DD, J=2,4, 5,6 Hz)6,91 (2H, d, J=9,2 Hz), 7,11 (2H, m), 7,29 (3H, m), to 7.67 (1H, d, J=2.4 Hz), 8,07 (1H, d, J=5.6 Hz), 8,32 (1H, m)8,64 (1H, c), 12,29 (1H, c).

ESI-MS (m/z): 581[M+H]+.

Example 178

4-(Azetidin-1-yl)piperidine-1-carboxylic acid [4-(3-fluoro-4-{3-[2-(4-forfinal)acetyl]ureido}of fenoc and)pyridine-2-yl]amide

After adding 10% palladium on coal (26,2 mg) to a solution of benzyl [4-(2-{[4-(azetidin-1-yl)piperidine-1-carbonyl]amino}pyridine-4-yloxy)-2-forfinal]carbamate (128 mg) in tetrahydrofuran (10 ml) the mixture is stirred for 16 hours at room temperature in a hydrogen atmosphere. The catalyst is filtered off and washed with tetrahydrofuran (4 ml)to give a solution of 4-(azetidin-1-yl)piperidine-1-carboxylic acid [4-(4-amino-3-pertenece)pyridine-2-yl]amide in tetrahydrofuran (approximately 14 ml) (ESI-MS (m/z): 386[M+H]+). The resulting solution was concentrated under reduced pressure to 4.5 ml and to a portion of the concentrate volume of 3.0 ml add 2-(4-forfinal)acetalization (0,25M solution in tetrahydrofuran, of 1.57 ml) at room temperature, after which the mixture is stirred for 0.5 hour at room temperature. Then to the reaction mixture at room temperature, add 2-(4-forfinal)acetalization (0,25M solution in tetrahydrofuran, to 0.89 ml) and stirred for 0.5 hour at room temperature. The reaction mixture was partitioned between saturated aqueous sodium bicarbonate and ethyl acetate. The organic layer is dried over anhydrous sodium sulfate. It is then concentrated under reduced pressure and purified column chromatography on silica gel (Fuji Silysia NH, eluent: heptane:ethyl acetate = 1:2, then ethyl acetate). Fraction, the content is the following target connection, concentrate under reduced pressure. The residue is purified by LC-MS (eluent: based on a mixture of water-acetonitrile with the addition of triperoxonane acid). The fractions containing the target compound, concentrate, immediately thereafter dried under reduced pressure and then partitioned between saturated aqueous sodium bicarbonate and ethyl acetate. The organic layer was washed with saturated saline and dried over anhydrous sodium sulfate. The organic layer is concentrated under reduced pressure, obtaining the crude target compound (30,3 mg). Add diethyl ether (1 ml), hexane (1 ml) and acetone (0.2 ml) to obtain the suspension of solids. The solid is filtered off and washed with diethyl ether. Then it is dried in the air flow, getting mentioned in the title compound (11.3 mg, 24,2%) as white powder.

Range1H-NMR (CDCl3) δ (ppm): 1,24-of 1.33 (2H, m), 1,68-of 1.73 (2H, m)to 2.06 (2H, m), of 2.21 (1H, m), 3,03 (2H, m), 3,19 (4H, m), of 3.73 (2H, c), 3,90 (2H, m), of 6.52 (1H, DD, J=2.0 a, 6,0 Hz), 6.87 in-6,92 (2H, m), was 7.08 (2H, m), 7,26-7,34 (3H, m), a 7.62 (1H, d, J=2.0 Hz), of 8.04 (1H, d, J=6.0 Hz), 8,15 (1H, m), of 8.90 (1H, m), of 10.72 (1H, Sirs).

ESI-MS (m/z): 565[M+H]+.

Example 179

4-{[(3S)-3-(Dimethylaminomethyl)pyrrolidin-1-yl]carbylamine}-6-(2-fluoro-4-{3-[2-(4-forfinal)acetyl]touraid}phenoxy)pyrimidine

After adding a solution of 2-(4-forfinal)acetylsalicylate in toluene (0,2M, 2.2 ml) to races is thief 4-(4-amino-2-pertenece)-6-{[(3S)-3-(dimethylaminomethyl)pyrrolidin-1-yl]carbylamine}pyrimidine (105 mg) and (+)-10-camphorsulfonic acid (65 mg) in ethanol (2.5 ml) at room temperature, the mixture is stirred for 1 hour. The reaction mixture is distributed between ethyl acetate and saturated aqueous sodium bicarbonate. The organic layer was washed with saturated aqueous sodium hydrogen carbonate and saturated saline, then dried over anhydrous sodium sulfate. The solvent is distilled off and the residue is purified column chromatography on silica gel (Fuji Silysia NH, eluent: ethyl acetate:heptane = 2:1, then ethyl acetate), obtaining specified in the header of the connection (of 60.5 mg, 38%) as white powder.

Range1H-NMR (CDCl3) δ (ppm): 1,72 (1H, m), 2,10 (1H, m), of 2.25 (6H, c), 2,29 of-2.32 (2H, m)of 2.50 (1H, m), 3,20 (1H, m), 3,40-3,70 (3H, m), 3,71 (2H, c), 7,10-7,40 (7H, m), of 7.70 (1H, c), 7,86 (1H, DD, J=2,4, 11.2 Hz), 8,32 (1H, c), 8,44 (1H, Sirs), 12,38 (1H, Sirs).

Example of getting 179-1

4-{[(3S)-3-(Dimethylaminomethyl)pyrrolidin-1-yl]carbylamine}-6-(2-fluoro-4-nitrophenoxy)pyrimidine

4-Amino-6-(2-fluoro-4-nitrophenoxy)pyrimidine (125 mg) was dissolved in tetrahydrofuran (2 ml) under nitrogen atmosphere. Add drop wise addition of triethylamine (0,167 ml) and phenylcarbamate (0,150 ml), cooling in a bath containing ice water. After stirring for 12 minutes at room temperature the solvent is distilled off under reduced pressure. To the resulting residue at room temperature under nitrogen atmosphere add a solution of dihydrochloride of (3S)-3-(dimethylaminomethyl)pyrrolidine (503 mg) in N,N-dimethylformamide (2.5 ml) and triethylamine (0,841 the l) and the mixture is stirred for 3.5 hours. The reaction mixture is distributed between ethyl acetate and water. The organic layer was washed with 1 N. aqueous sodium hydroxide solution and saturated saline, then dried over anhydrous sodium sulfate. The solvent is distilled off under reduced pressure, then the residue purified column chromatography on silica gel (Fuji Silysia NH, eluent, ethyl acetate:heptane = 2:1, then ethyl acetate), obtaining mentioned in the title compound (124 mg, 61%) as a colourless oil.

ESI-MS (m/z): 427[M+Na]+.

Example of getting 179-2

4-(4-Amino-2-pertenece)-6-{[(3S)-3-(dimethylaminomethyl)pyrrolidin-1-yl]carbylamine}pyrimidine

4-{[(3S)-3-(Dimethylaminomethyl)pyrrolidin-1-yl]carbylamine}-6-(2-fluoro-4-nitrophenoxy)pyrimidine (124 mg) was dissolved in tetrahydrofuran (15 ml). After adding 20% palladium hydroxide on coal (86 mg), the mixture is stirred overnight in a hydrogen atmosphere. The catalyst is filtered off and washed with tetrahydrofuran. The filtrate and washings are combined and concentrated under reduced pressure, after which the resulting residue is dried under reduced pressure, obtaining mentioned in the title compound (105 mg, 91%) as oil pale yellow color.

ESI-MS (m/z): 397[M+Na]+.

Example 180

4-{[4-(Dimethylaminomethyl)piperidine-1-yl]carbylamine}-6-(2-fluoro-4-{3-[2-(4-forfinal)acetyl]touraid}phenoxy)pyrimidine

After adding the Astor 2-(4-forfinal)acetylsalicylate in toluene (0,2M, 3.0 ml) to a solution of 4-(4-amino-2-pertenece)-6-{[4-(dimethylaminomethyl)piperidine-1-yl]carbylamine}pyrimidine (118 mg) and (+)-10-camphorsulfonic acid (70,6 mg) in ethanol (3.0 ml) at room temperature, the mixture is stirred for 2 hours. The reaction mixture is distributed between ethyl acetate and saturated aqueous sodium bicarbonate. The organic layer was washed with saturated aqueous sodium hydrogen carbonate and saturated saline, then dried over anhydrous sodium sulfate. The solvent is distilled off and the residue is purified column chromatography on silica gel (Fuji Silysia NH, eluent: ethyl acetate:heptane = 4:1), obtaining mentioned in the title compound (70.0 mg, 40%) as white powder.

Range1H-NMR (CDCl3) δ (ppm): 1,10-1,40 (2H, m)to 1.70 (1H, m), 1,80-1,90 (2H, m), 2,10-of 2.15 (2H, m), 2,22 (6H, c), 2,85-of 3.00 (2H, m), 3,71 (2H, c), 4,05-to 4.15 (2H, m), 7,10-7,40 (7H, m), of 7.64 (1H, d, J=0.8 Hz), 7,86 (1H, DD, J=2,4, 11.2 Hz), with 8.33 (1H, d, J=0.8 Hz), 8,49 (1H, Sirs), 12,38 (1H, Sirs).

ESI-MS (m/z): 584[M+H]+.

Example of getting 180-1

4-{[4-(Dimethylaminomethyl)piperidine-1-yl]carbylamine}-6-(2-fluoro-4-nitrophenoxy)pyrimidine

4-Amino-6-(2-fluoro-4-nitrophenoxy)pyrimidine (125 mg) was dissolved in tetrahydrofuran (2 ml) under nitrogen atmosphere. Add drop wise addition of triethylamine (0,167 ml) and phenylcarbamate (0,150 ml), cooling in a bath containing ice water. After stirring for 10 minutes at the room for the Noah temperature, the solvent is distilled off under reduced pressure. To the resulting residue at room temperature under nitrogen atmosphere add a solution of dihydrochloride of 4-(dimethylaminomethyl)piperidine (538 mg) in N,N-dimethylformamide (2.5 ml) and triethylamine (0,841 ml) and the mixture is stirred for 2 hours. The reaction mixture is distributed between ethyl acetate and water. The organic layer was washed with 1 N. aqueous sodium hydroxide solution and saturated saline, then dried over anhydrous sodium sulfate. The solvent is distilled off under reduced pressure, then the residue purified column chromatography on silica gel (Fuji Silysia NH, eluent: ethyl acetate:heptane = 2:1, then ethyl acetate), obtaining mentioned in the title compound (136 mg, 65%) as white crystals.

Range1H-NMR (CDCl3) δ (ppm): 1,20-1,40 (2H, m), 1,72 (1H, m), 1,80-1,90 (2H, m), 2,10-of 2.20 (2H, m), 2,22 (6H, c), 2,90-of 3.00 (2H, m), 4,05-to 4.15 (2H, m), 7,41 (1H, m), 7,45 (1H, Sirs), 7,73 (1H, d, J=0.8 Hz), 8,06-8,16 (2H, m), 8,32 (1H, d, J=0.8 Hz).

Example of getting 180-2

4-(4-Amino-2-pertenece)-6-{[4-(dimethylaminomethyl)piperidine-1-yl]carbylamine}pyrimidine

4-{[4-(Dimethylaminomethyl)piperidine-1-yl]carbylamine}-6-(2-fluoro-4-nitrophenoxy)pyrimidine (136 mg) was dissolved in tetrahydrofuran (15 ml). After adding 20% palladium hydroxide on coal (100 mg) the mixture is stirred overnight in a hydrogen atmosphere. The catalyst is filtered off and washed with tetrahydrofuran. The filtrate and washings about is United by, concentrate under reduced pressure and the resulting residue is dried under reduced pressure, obtaining mentioned in the title compound (118 mg, 94%) as a colourless oil.

ESI-MS (m/z): 389[M+H]+.

Example 181

4-{[4-(2-Dimethylaminoethyl)piperazine-1-yl]carbylamine}-6-(2-fluoro-4-{3-[2-(4-forfinal)acetyl]touraid}phenoxy)pyrimidine

After adding a solution of 2-(4-forfinal)acetylsalicylate in toluene (0,2M, 3.5 ml) to a solution of 4-(4-amino-2-pertenece)-6-{[4-(2-dimethylaminoethyl)piperazine-1-yl]carbylamine}pyrimidine (150 mg) and (+)-10-camphorsulfonic acid (173 mg) in ethanol (3.5 ml) at room temperature, the mixture is stirred for 2 hours. The reaction mixture is distributed between ethyl acetate and saturated aqueous sodium bicarbonate. The organic layer was washed with saturated aqueous sodium hydrogen carbonate and saturated saline solution in that order and dried over anhydrous sodium sulfate. The solvent is distilled off and the residue is purified column chromatography on silica gel (Fuji Silysia NH, eluent: ethyl acetate, then ethyl acetate:methanol = 95:5), receiving specified in the header connection (84,8 mg, 38%) as white powder.

Range1H-NMR (CDCl3) δ (ppm): and 2.26 (6H, c), 2,42-2,58 (8H, m), 3,52-of 3.60 (4H, m), 3,71 (2H, c), 7,09-7,40 (7H, m), 7,63 (1H, d, J=0.8 Hz), 7,86 (1H, DD, J=2,4, 12.0 Hz), with 8.33 (1H, d, J=0.8 Hz), 8,49 (1H, Sirs), 12,38 (1H, Sirs).

ESI-MS (m/z: 599[M+H] +.

Example of getting 181-1

4-{[4-(2-Dimethylaminoethyl)piperazine-1-yl]carbylamine}-6-(2-fluoro-4-nitrophenoxy)pyrimidine

4-Amino-6-(2-fluoro-4-nitrophenoxy)pyrimidine (125 mg) was dissolved in tetrahydrofuran (2 ml) under nitrogen atmosphere. Add drop wise addition of triethylamine (0,174 ml) and phenylcarbamate (of) 0.157 ml), cooling in a bath containing ice water. After stirring for 20 minutes at room temperature the solvent is distilled off under reduced pressure. To the resulting residue at room temperature under nitrogen atmosphere add a solution of 1-(2-dimethylaminoethyl)piperazine (393 mg) in N,N-dimethylformamide (2.5 ml) and the mixture is stirred for 2.5 hours. The reaction mixture is distributed between ethyl acetate and water. The organic layer was washed with 1 N. aqueous sodium hydroxide solution and saturated saline solution in that order and dried over anhydrous sodium sulfate. The solvent is distilled off under reduced pressure and then the residue is purified column chromatography on silica gel (Fuji Silysia NH, eluent: ethyl acetate, then ethyl acetate:methanol = 95:5), receiving specified in the title compound (167 mg, 77%) as a powder pale yellow color.

Range1H-NMR (CDCl3) δ (ppm): and 2.26 (6H, c), 2,40-2,60 (8H, m), 3,50-3,60 (4H, m), 7,39 was 7.45 (2H, m), 7,73 (1H, d, J=0.8 Hz), 8.07-a of 8.15 (2H, m), 8,32 (1H, d, J=0.8 Hz).

Example of getting 181-2

4-(4-Amino-2-pertenece)-6-{[4-(2-DIMET aminoethyl)piperazine-1-yl]carbylamine}pyrimidine

4-{[4-(2-Dimethylaminoethyl)piperazine-1-yl]carbylamine}-6-(2-fluoro-4-nitrophenoxy)pyrimidine (167 mg) was dissolved in tetrahydrofuran (16 ml). After adding 20% palladium hydroxide on coal (108 mg) the mixture is stirred overnight in a hydrogen atmosphere. The catalyst is filtered off and washed with tetrahydrofuran. The filtrate and washings are combined to a concentrated under reduced pressure and the resulting residue is dried under reduced pressure, obtaining mentioned in the title compound (150 mg, 97%) as a powder pale yellow color.

ESI-MS (m/z): 404[M+H]+.

Example 182

4-{2-Fluoro-4-[3-(2-phenylacetyl)touraid]phenoxy}-2-{[4-(1-methylpiperazin-4-yl)piperidine-1-yl]carbylamine}pyridine

After adding a solution of 2-phenylacetonitrile in toluene (0,2M, 2.0 ml) to a solution of 4-(4-amino-2-pertenece)-2-{[4-(1-methylpiperazin-4-yl)piperidine-1-yl]carbylamine}pyridine (85 mg) and (+)-10-camphorsulfonic acid (92 mg) in ethanol (2.0 ml) at room temperature, the mixture is stirred for 25 minutes. The reaction mixture is distributed between ethyl acetate and saturated aqueous sodium bicarbonate. The organic layer was washed with saturated aqueous sodium hydrogen carbonate and saturated saline, then dried over anhydrous sodium sulfate. The solvent is distilled off and the residue is purified column chromatography on silica gel (Fji Silysia NH, eluent: ethyl acetate:methanol = 98:2 to 95:5), receiving specified in the header connection (up to 30.5 mg, 25%) as white powder.

Range1H-NMR (CDCl3) δ (ppm): 1,50-of 1.95 (5H, m), 2,28 (3H, c), a 2.36-2,70 (8H, m), 2,89 (2H, m), 3,74 (2H, c), Android 4.04-4,16 (2H, m), 6,53 (1H, DD, J=2,4, 5,6 Hz), 7,10-to 7.50 (8H, m), a 7.62 (1H, d, J=2.4 Hz), 7,89 (1H, DD, J=2,4, and 11.6 Hz), with 8.05 (1H, d, J=5.6 Hz), of 8.47 (1H, Sirs), to 12.44 (1H, Sirs).

ESI-MS (m/z): 606[M+H]+.

Example of getting 182-1

4-(2-Fluoro-4-nitrophenoxy)-2-{[4-(1-methylpiperazin-4-yl)piperidine-1-yl]carbylamine}pyridine

2-Amino-4-(2-fluoro-4-nitrophenoxy)pyridine (100 mg) dissolved in tetrahydrofuran (2 ml) under nitrogen atmosphere. Add drop wise addition of triethylamine (0,140 ml) and phenylcarbamate (0,126 ml), cooling in a bath containing ice water. After stirring for 20 minutes at room temperature the solvent is distilled off under reduced pressure. To the resulting residue at room temperature under nitrogen atmosphere add a solution of 4-(1-methylpiperazin-4-yl)piperidine (368 mg) in N,N-dimethylformamide (2.0 ml) and the mixture is stirred over night. The reaction mixture is distributed between ethyl acetate and water. The organic layer was washed with 1 N. aqueous sodium hydroxide solution and saturated saline, then dried over anhydrous sodium sulfate. The solvent is distilled off under reduced pressure and then the residue is purified column chromatography on silica gel (Fuji Silysi NH, eluent: ethyl acetate:methanol = 98:2 to 95:5), receiving specified in the title compound (138 mg, 75%) as a powder pale yellow color.

Range1H-NMR (CDCl3) δ (ppm): 1,60-2,00 (5H, m), 2,28 (3H, c), 2,40-of 3.00 (10H, m), 4,00-4,20 (2H, m), only 6.64 (1H, DD, J=2,4, 5,6 Hz), 7,20-7,40 (2H, m), of 7.70 (1H, d, J=2.4 Hz), 8,00-to 8.20 (3H, m).

Example of getting 182-2

4-(4-Amino-2-pertenece)-2-{[4-(1-methylpiperazin-4-yl)piperidine-1-yl]carbylamine}pyridine

4-(2-Fluoro-4-nitrophenoxy)-2-{[4-(1-methylpiperazin-4-yl)piperidine-1-yl]carbylamine}pyridine (138 mg) was dissolved in tetrahydrofuran (30 ml). After adding 20% palladium hydroxide on coal (89 mg) the mixture is stirred overnight in a hydrogen atmosphere. The catalyst is filtered off and washed with tetrahydrofuran. The filtrate and washings are combined to a concentrated under reduced pressure and the resulting residue is dried under reduced pressure, obtaining mentioned in the title compound (85 mg, 66%) as a powder pale yellow color.

ESI-MS (m/z): 429[M+H]+.

Example 183

1-[1-(2-Dimethylaminoethyl)piperidine-4-yl]-3-[4-(3-fluoro-4-{3-[2-(4-forfinal)acetyl]touraid}phenoxypyridine-2-yl)-1-metalmachine

After adding 20% palladium hydroxide on coal (20 mg) to a solution of benzyl [4-(2-{3-[1-(2-dimethylaminoethyl)piperidine-4-yl]-3-methylurea}pyridine-4-yloxy)-2-forfinal]carbamate (51.3 mg) in tetrahydrofuran (5.0 ml) and the mixture is stirred for 6 hours at room themes is the temperature value in an atmosphere of hydrogen. Then the catalyst is filtered off. The filtrate is concentrated and receiving 3-[4-(4-amino-3-pertenece)pyridine-2-yl]-1-[1-(2-dimethylaminoethyl)piperidine-4-yl]-1-metalmachine (ESI-MS (m/z): 431 [M+H]+in the form of oil pale yellow color. The resulting substance was dissolved in ethanol (0.68 ml), then add (1S)-(+)-10-camphorsulfonic acid (40,1 mg) and the mixture stirred for 5 minutes at room temperature. After adding 2-(4-forfinal)acetylsalicylate (0,2M solution in toluene, 0,682 ml) the mixture was stirred at room temperature for 1 hour. After adding another portion of 2-(4-forfinal)acetylsalicylate (0,2M solution in toluene, 1,24 ml) the mixture is again stirred at room temperature for 1 hour. After adding another portion of 2-(4-forfinal)acetylsalicylate (0,2M solution in toluene, 0,205 ml) stirring is continued at room temperature for 1 hour. Then add the last portion of 2-(4-forfinal)acetylsalicylate (0,2M solution in toluene, 0,205 ml) and the mixture is stirred at room temperature for 3 hours. The reaction mixture is distributed between ethyl acetate and saturated aqueous sodium bicarbonate. The organic layer is dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue is purified by LC-MS (eluent: sysetm acetonitrile-water-triperoxonane KIS the PTA). The fractions containing the target compound, concentrated and the residue distributed between ethyl acetate and saturated aqueous sodium bicarbonate. The organic layer is dried over anhydrous sodium sulfate and concentrated under reduced pressure. To the obtained residue, add a mixture of hexane:ethyl acetate = 5:1 to precipitate a solid. The solid is filtered, washed with hexane and dried, obtaining mentioned in the title compound (8.5 mg, 14.9 per cent) in the form of a powder pale yellow color.

Range1H-NMR (CDCl3) δ (ppm): of 1.65 (2H, m)to 1.79 (2H, m), 2,12 (2H, m)to 2.29 (6H, c), 2,49 (4H, m), 2,89 (3H, c), a 3.01 (2H, m), and 3.72 (2H, c), 4,17 (1H, m), to 6.57 (1H, DD, J=2,4, 6,0 Hz)6,91 (2H, d, J=8,8 Hz), 7,11 (2H, m), 7.23 percent-7,31 (3H, m), 7,74 (1H, d, J=2.4 Hz), of 8.09 (1H, d, J=6.0 Hz), 8,32 (1H, m), 12,30 (1H, c).

ESI-MS (m/z): 626[M+H]+.

Example of getting 183-1

Tert-butyl [1-(2-dimethylaminoacetyl)piperidine-4-yl]carbamate

After adding N,N-dimethylglycine (2,97 g), 1-hydroxybenzotriazole (to 3.89 g) and hydrochloride of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (5,27 g) to a solution of 4-(tert-butoxycarbonylamino)piperidine (5.0 g) in N,N-dimethylformamide (70 ml), the mixture is stirred for 46 hours at room temperature in a nitrogen atmosphere. To the reaction mixture are added ethyl acetate (400 ml), saturated brine (200 ml) and 1 N. aqueous sodium hydroxide solution (50 ml) and stirred at room temperature for 30 minutes, the donkey and the mixture evenly. The aqueous layer was extracted with ethyl acetate. The organic layers are combined, washed 1 N. aqueous sodium hydroxide solution and saturated saline solution in that order and then dried over anhydrous sodium sulfate. The dried organic layer is concentrated under reduced pressure, obtaining specified in the header connection (8,03 g, quantitative yield) as colorless crystals.

ESI-MS (m/z): 286[M+H]+.

Example of getting 183-2

Trihydrochloride N-[1-(2-dimethylaminoethyl)piperidine-4-yl]-N-methylamine

A solution of tert-butyl [1-(2-dimethylaminoacetyl)piperidine-4-yl]carbamate (702 mg) in tetrahydrofuran (10.5 ml) is stirred while cooling in a bath with ice in a nitrogen atmosphere. Add the aluminum lithium hydride (280 mg) and the mixture is stirred in a bath with ice for 15 minutes and at room temperature for 15 minutes. The reaction mixture is heated under reflux for 8 hours at 100°C in nitrogen atmosphere. Then the reaction mixture is cooled on ice. Add water (0,280 ml), 5 N. aqueous sodium hydroxide solution (0,280 ml) and water (0,840 ml) in that order, after which the mixture is stirred for 1 hour. The insoluble matter is filtered and to the filtrate is added 4 n hydrochloric acid in ethyl acetate (1.23 ml). The resulting mixture was concentrated, obtaining mentioned in the title compound (673 mg, quantitative yield) in the form of crystals of pale yellow color.

Range1H-NMR (CD3OD) δ (ppm): 1,70-1,80 (2H, m)2,07 (2H, m), 2,19 (2H, m), 2,70 (3H, c), by 2.73 (2H, m), 2,89 (6H, c)3,02-3,13 (3H, m), 3,26 (2H, m).

ESI-MS (m/z): 186 [M+H]+.

Example of getting 183-3

Benzyl [4-(2-{3-[1-(2-dimethylaminoethyl)piperidine-4-yl]-3-methylurea}pyridine-4-yloxy)-2-forfinal]carbamate

After adding triethylamine (to 0.127 ml) and phenylcarbamate (0.100 ml) to a solution of benzyl [4-(2-aminopyridine-4-yloxy)-2-forfinal]carbamate (113 mg) in tetrahydrofuran (5.0 ml) and the mixture is stirred for 30 minutes at room temperature in a nitrogen atmosphere. The reaction mixture is distributed between ethyl acetate (50 ml) and saturated saline (30 ml). The organic layer is dried over anhydrous sodium sulfate and then concentrated under reduced pressure. To the obtained residue, add suspension (4 ml), obtained by adding tetrahydrofuran (6.0 ml) and triethylamine (2.0 ml) to trihydrochloride N-[1-(2-dimethylaminoethyl)piperidine-4-yl]-N-methylamine (673 mg), and the resulting mixture was stirred at room temperature for 27 hours. To the reaction mixture are added ethyl acetate (30 ml) and 1 N. aqueous sodium hydroxide solution (10 ml) and stirring is carried out for 5 hours at room temperature. Add saturated salt solution and the mixture extracted with ethyl acetate. Then the aqueous layer was extracted with ethyl acetate. The organic layers are combined and about what to see 1 N. aqueous solution of sodium hydroxide and saturated saline in this order, then dried over anhydrous sodium sulfate. The dried organic layer is concentrated and the residue purified column chromatography on silica gel (Fuji Silysia NH, eluent: ethyl acetate:methanol = 20:1 to 10:1). The fractions containing the target compound, concentrate, and get a white solid. Add methanol (3 ml) and 5 N. aqueous sodium hydroxide solution (1 ml), after which the mixture was stirred at room temperature for 1 hour. Then the reaction mixture is distributed between ethyl acetate and saturated salt solution. The organic layer was washed with saturated saline and dried over anhydrous sodium sulfate. Then the organic layer concentrated. The residue is purified by LC-MS (eluent: system acetonitrile-water-triperoxonane acid). Respectively the fractions containing the target compound concentrate. The residue is distributed between ethyl acetate and saturated aqueous sodium bicarbonate. The organic layer is dried over anhydrous sodium sulfate. Then his focus, getting mentioned in the title compound (51.3 mg, 28,4%) as a colourless oil.

Range1H-NMR (CDCl3) δ (ppm): of 1.64 (2H, m), of 1.78 (2H, m), 2,11 (2H, m), and 2.27 (6H, c), 2,48 (4H, m), is 2.88 (3H, c), a 3.01 (2H, m)to 4.16 (1H, m), 5,23 (2H, c), of 6.52 (1H, DD, J=2,4, 6,0 Hz), 6,85-6,9 (3H, m), 7,20 (1H, c), 7,33-the 7.43 (5H, m), 7,68 (1H, d, J=2.4 Hz), with 8.05 (1H, d, J=6.0 Hz), 8,12 (1H, Sirs).

ESI-MS (m/z): 565[M+H]+.

Example 184

1-[1-(2-Dimethylaminoethyl)piperidine-4-yl]-3-[6-(2-fluoro-4-{3-[2-(4-forfinal)acetyl]touraid}phenoxy)pyrimidine-4-yl]-1-metalmachine

After addition of (1S)-(+)-10-camphorsulfonic acid (101 mg) to a solution of 3-[6-(4-amino-2-pertenece)pyrimidine-4-yl]-1-[1-(2-dimethylaminoethyl)piperidine-4-yl]-1-metalmachine (110 mg) in ethanol (2.0 ml), the mixture is stirred for 15 minutes at room temperature. After adding 2-(4-forfinal)acetylsalicylate (a 3.06 ml, 0,25M solution in toluene), the mixture is stirred at room temperature for another 1 hour. The reaction mixture was partitioned between saturated aqueous sodium hydrogen carbonate (10 ml) and ethyl acetate (30 ml). The organic layer was washed with saturated saline and dried over anhydrous sodium sulfate. The dried organic layer is concentrated and the residue purified column chromatography on silica gel (Fuji Silysia NH, eluent: ethyl acetate, then ethyl acetate:methanol = 20:1 to 10:1). The fractions containing the target compound concentrate. The obtained solid is suspended in a mixture of diethyl ether:hexane = 1:1. The precipitate is filtered and then washed with diethyl ether, obtaining mentioned in the title compound (50.5 mg, 31,6%) in the form of a powder pale yellow color.

Range1H-YAM who (CDCl 3) δ (ppm): 1.69 in (2H, m)and 1.83 (2H, m), of 2.15 (2H, m), is 2.30 (6H, c), of 2.51 (4H, m), of 2.92 (3H, c), 3,05 (2H, m), 3,71 (2H, c), 4,19 (1H, m), 7,10 (2H, m), 7,20-7,37 (5H, m), 7,68 (1H, c), 7,86 (1H, DD, J=2,4, a 7.6 Hz), a 8.34 (1H, c), and 8.50 (1H, Sirs), 12,38 (1H, c).

ESI-MS (m/z): 627[M+H]+.

Example of getting 184-1

N-[1-(2-Dimethylaminoethyl)piperidine-4-yl]-N-methylamine

A solution of tert-butyl [1-(2-dimethylaminoacetyl)piperidine-4-yl]carbamate (702 mg) in tetrahydrofuran (10.5 ml) is stirred while cooling in a bath with ice in a nitrogen atmosphere. Add the aluminum lithium hydride (280 mg), after which the mixture is stirred in a bath with ice for 15 minutes and at room temperature for 15 minutes. The reaction mixture is heated under reflux for 11 hours at 100°C in nitrogen atmosphere. Then the reaction mixture is cooled in a bath with ice. Add water (2.8 ml), 5 N. aqueous sodium hydroxide solution (2.8 ml) and water (14,0 ml) in that order, after which the mixture is stirred for 2 hours. The insoluble matter is filtered off. The filtrate is concentrated and receive specified in the header connection (4,65 g, quantitative yield) as a yellow oil.

Range1H-NMR (CDCl3) δ (ppm): 1,34 was 1.43 (2H, m), 1,87-1,90 (2H, m), 2,02-of 2.08 (2H, m), of 2.25 (6H, c), 2,31-of 2.50 (7H, m), 2,90 (2H, m), 3,14-of 3.27 (1H, m).

ESI-MS (m/z): 186[M+H]+.

Example of getting 184-2

3-[6-(2-Fluoro-4-nitrophenoxy)pyrimidine-4-yl]-1-[1-(2-dimethylaminoethyl)piperidine-4-yl]-1-metalmachine

After adding triethylamine (0,266 ml) and phenylcarbamate (0,221 ml) to a solution of 6-(2-fluoro-4-nitrophenoxy)pyrimidine-4-ylamine (200 mg) in tetrahydrofuran (10.0 ml) and the mixture is stirred for 30 minutes at room temperature in a nitrogen atmosphere. Then the reaction mixture was concentrated. After adding to the residue N,N-dimethylformamide (6.0 ml) and N-[1-(2-dimethylaminoethyl)piperidine-4-yl]-N-methylamine (593 mg), the mixture is stirred for 8 hours at room temperature. To the reaction mixture are added ethyl acetate (30 ml) and 1 N. aqueous sodium hydroxide solution (10 ml), then stirred at room temperature for 5 hours. Add saturated salt solution and the mixture extracted with ethyl acetate. The aqueous layer was extracted with ethyl acetate. The organic layers are then combined and washed with 1 N. aqueous sodium hydroxide solution and saturated saline solution in this order, then dried over anhydrous sodium sulfate. The dried organic layer is concentrated and the residue purified column chromatography on silica gel (Fuji Silysia NH, eluent: ethyl acetate:methanol = 20:1 to 10:1). The fractions containing the target compound concentrate. The obtained solid is suspended in a mixture of diethyl ether-hexane (1:1) and the supernatant removed. The solid is dried and receive specified in the title compound (240 mg, 65,0%) in the form then the scale of pale yellow color.

Range1H-NMR (CDCl3) δ (ppm): 1,67 (2H, m), of 1.85 (2H, m), of 2.15 (2H, m), is 2.30 (6H, c), 2,52 (4H, m)to 2.94 (3H, c), 3,06 (2H, m), 4,20 (1H, m), of 7.36 (1H, c), 7,42 (1H, m), to 7.77 (1H, d, J=0.8 Hz), 8,08-8,24 (2H, m), with 8.33 (1H, d, J=0.8 Hz).

ESI-MS (m/z): 462[M+H]+.

Example nexposure 184-3

3-[6-(4-Amino-2-pertenece)pyrimidine-4-yl]-1-[1-(2-dimethylaminoethyl)piperidine-4-yl]-1-metalmachine

After adding 20% palladium hydroxide on coal (18.3 mg) to a solution of 3-[6-(2-fluoro-4-nitrophenoxy)pyrimidine-4-yl]-1-[1-(2-dimethylaminoethyl)piperidine-4-yl]-1-metalmachine (240 mg) in tetrahydrofuran (10 ml) the mixture is stirred for a 15.5 hours at room temperature in a hydrogen atmosphere. The catalyst is filtered off and washed with methanol. Then the filtrate is concentrated and get listed in the title compound (220 mg, 98,0%) as amorphous yellow substance.

ESI-MS (m/z): 432[M+H]+.

Example 185

4-{2-Fluoro-4-[3-(2-phenylacetyl)touraid]phenoxy}-2-{[4-(4-hydroxypiperidine-1-yl)piperidine-1-yl]carbylamine}pyridine

After adding a solution of 2-phenylacetonitrile in toluene (0,2M, 4,0 ml) to a solution of 4-(4-amino-2-pertenece)-2-{[4-(4-hydroxypiperidine-1-yl)piperidine-1-yl]carbylamine}pyridine (164 mg) and (+)-10-camphorsulfonic acid (85 mg) in ethanol (4.0 ml) at room temperature, the mixture is stirred for 1 hour. The reaction mixture is distributed between ethyl acetate and saturated aqueous guide is carbonate sodium. The organic layer was washed with saturated aqueous sodium hydrogen carbonate and saturated saline solution in that order and dried over anhydrous sodium sulfate. The solvent is distilled off and the residue is purified column chromatography on silica gel (Fuji Silysia NH, eluent: ethyl acetate:methanol = 98:2 to 95:5), receiving specified in the title compound (127 mg, 57%) as white powder.

Range1H-NMR (CDCl3) δ (ppm): 1,40-2,00 (8H, m), 2,25-to 2.40 (2H, m), 2.49 USD (1H, m), 2,75-2,90 (4H, m), 3,70 (1H, m), 3,74 (2H, c), 4,05-4,20 (2H, m), 6,53 (1H, DD, J=2,4, 5,6 Hz), 7,10-to 7.50 (8H, m), a 7.62 (1H, d, J=2.4 Hz), 7,89 (1H, DD, J=2,4, and 11.6 Hz), of 8.04 (1H, d, J=5.6 Hz), 8,53 (1H, Sirs), to 12.44 (1H, Sirs).

ESI-MS (m/z): 607[M+H]+.

Example of getting 185-1

4-(2-Fluoro-4-nitrophenoxy)-2-{[4-(4-hydroxypiperidine-1-yl)piperidine-1-yl]carbylamine}pyridine

2-Amino-4-(2-fluoro-4-nitrophenoxy)pyridine (100 mg) dissolved in tetrahydrofuran (2 ml) under nitrogen atmosphere. Add drop wise addition of triethylamine (0,140 ml) and phenylcarbamate (0,126 ml), cooling in a bath containing ice water. After stirring for 20 minutes at room temperature the solvent is distilled off under reduced pressure. To the resulting residue at room temperature under nitrogen atmosphere add a solution of 4-(4-hydroxypiperidine-1-yl)piperidine (412 mg) in N,N-dimethylformamide (5.0 ml) and the mixture is stirred over night. The reaction mixture is partitioned between etelaat the Tom and water. The organic layer was washed with 1 N. aqueous sodium hydroxide solution and saturated saline solution in this order, then dried over anhydrous sodium sulfate. The solvent is distilled off under reduced pressure and then the residue is purified column chromatography on silica gel (Fuji Silysia NH, eluent: ethyl acetate:methanol = 98:2 to 95:5), receiving specified in the title compound (168 mg, 91%) as a powder pale yellow color.

Range1H-NMR (CDCl3) δ (ppm): 1,40-2,00 (8H, m), 2,31 (2H, m), 2,52 (1H, m), 2,70-2,95 (4H, m), 3,70 (1H, m), 4,00-4,20 (2H, m), only 6.64 (1H, DD, J=2,4, 5,6 Hz), 7,20-7,40 (2H, m), of 7.70 (1H, d, J=2.4 Hz), 8,00-to 8.20 (3H, m).

Example of getting 185-2

4-(4-Amino-2-pertenece)-2-{[4-(4-hydroxypiperidine-1-yl)piperidine-1-yl]carbylamine}pyridine

4-(2-Fluoro-4-nitrophenoxy)-2-{[4-(4-hydroxypiperidine-1-yl)piperidine-1-yl]carbylamine}pyridine (168 mg) was dissolved in tetrahydrofuran (20 ml). After adding 20% palladium hydroxide on coal (103 mg), the mixture is stirred overnight in a hydrogen atmosphere. The catalyst is filtered off and washed with tetrahydrofuran. The filtrate and washings are combined to a concentrated under reduced pressure and the resulting residue is dried under reduced pressure, obtaining mentioned in the title compound (164 mg) in the form of a powder pale yellow color.

ESI-MS (m/z): 430[M+H]+.

Example 186

4-(Dimethylaminomethyl)piperidine-1-carboxylic acid {6-[2-ft is R-4-(3-phenylacetylamino)phenoxy]pyrimidine-4-yl}amide

After adding tetrahydrofuran (2 ml) and methanol (2 ml) to 4-(dimethylaminomethyl)piperidine-1-carboxylic acid [6-(2-fluoro-4-nitrophenoxy)pyrimidine-4-yl]amide (88 mg) in a nitrogen atmosphere, add 10% palladium on coal (45 mg), the atmosphere in the reaction vessel is replaced with hydrogen and the mixture is stirred for 9 hours. Then the atmosphere in the reaction vessel is replaced by nitrogen, the catalyst is filtered off and washed with methanol. The filtrate is concentrated under reduced pressure, obtaining the crude 4-(dimethylaminomethyl)piperidine-1-carboxylic acid [6-(4-amino-2-pertenece)pyrimidine-4-yl]amide (90 mg) as an amorphous substance pale yellow color.

After dissolving the crude product (81,6 mg) in ethanol (1 ml) under nitrogen atmosphere add D-10-camphorsulfonic acid (49 mg) and the mixture stirred for 5 minutes. To the reaction mixture to 0,5M solution of 2-phenylacetonitrile in toluene (0.63 ml) and the mixture is stirred for 1 hour. Then the reaction mixture is distributed between ethyl acetate (50 ml) and saturated aqueous sodium hydrogen carbonate (30 ml). The organic layer was washed with saturated aqueous sodium hydrogen carbonate (30 ml), water (30 ml) and saturated saline (30 ml) in that order, then dried over anhydrous sodium sulfate. The solvent is distilled off under reduced pressure and the resulting residue is purified column chromatography on silica gel (Fuji Silysia NH, eluent: heptane:ethyl acetate = 1:1 to 2:3). The fractions containing the target compound are concentrated under reduced pressure, and then to the obtained residue is added diethyl ether (1.0 ml) and hexane (3.0 ml) to give a suspension. The solid is filtered off, dried in a stream of air, which is specified in the header connection (34,0 mg, 28.6 per cent) in the form of white powder.

Range1H-NMR (CDCl3) δ (ppm): 1,50-of 1.56 (3H, m), of 1.85 (2H, m), and 2.14 (2H, t, J=7.2 Hz), 2,22 (6H, c), with 2.93 (2H, m), 3,74 (2H, Sirs), 4.09 to (2H, m), 7,16-to 7.50 (8H, m), of 7.64 (1H, m), 7,86 (1H, DD, J=2,4, and 11.6 Hz), with 8.33 (1H, m,), 8,44 (1H, Sirs), 12,43 (1H, Sirs).

ESI-MS (m/z): 566[M+H]+.

Example 187

4-(2-Dimethylaminoethyl)piperazine-1-carboxylic acid {6-[2-fluoro-4-(3-phenylacetylamino)phenoxy]pyrimidine-4-yl}amide

After adding tetrahydrofuran (2 ml) and methanol (2 ml) to 4-(2-dimethylaminoethyl)piperazine-1-carboxylic acid [6-(2-fluoro-4-nitrophenoxy)pyrimidine-4-yl]amide (94 mg) in a nitrogen atmosphere, add 10% palladium on coal (46 mg), the atmosphere in the reaction vessel is replaced with hydrogen and the mixture is stirred for 9 hours. Then the atmosphere in the reaction vessel is replaced by nitrogen, the catalyst is filtered off and washed with methanol. The filtrate is concentrated under reduced pressure, obtaining the crude 4-(2-dimethylaminoethyl)piperazine-1-carboxylic acid [6-(4-amino-2-pertenece)pyrimidine-4-yl]amide (91 mg) as amorphous, washes the VA pale yellow color.

After dissolving the crude product (81 mg) in ethanol (1 ml) under nitrogen atmosphere add D-10-camphorsulfonic acid (51 mg) and the mixture stirred for 5 minutes. To the reaction mixture to 0,5M solution of 2-phenylacetonitrile in toluene (0,651 ml) and stirred for 1 hour. The reaction mixture is distributed between ethyl acetate (50 ml) and saturated aqueous sodium hydrogen carbonate (30 ml). The organic layer was washed with saturated aqueous sodium hydrogen carbonate (30 ml), water (30 ml) and saturated saline (30 ml) in that order, then dried over anhydrous sodium sulfate. The solvent is distilled off under reduced pressure and then the resulting residue is purified column chromatography on silica gel (Fuji Silysia NH, eluent: heptane:ethyl acetate = 1:5, then ethyl acetate). The fractions containing the target compound are concentrated under reduced pressure, and then to the obtained residue is added diethyl ether (1.0 ml) and hexane (3.0 ml) to obtain the suspension of solids. The solid is filtered off, dried in a stream of air, which is specified in the header connection (to 47.8 mg, 37.9%) in the form of white powder.

Range1H-NMR (CDCl3) δ (ppm): of 2.27 (6H, c)to 2.46 (2H, m), 2,53 (6H, m), 3,55 (4H, m), 3,74 (2H, c), 7,15-7,52 (8H, m), 7,63 (1H, m), 7,86 (1H, DD, J=2,8, and 11.6 Hz), with 8.33 (1H, m), 8,43 (1H, Sirs), 12,42 (1H, Sirs).

ESI-MS (/z): 581[M+H] +.

Example 188

2-{[4-(Dimethylaminomethyl)piperidine-1-yl]carbylamine}-4-(4-{3-[2-(4-forfinal)acetyl]touraid}phenoxy)pyridine

After adding a solution of 2-(4-forfinal)acetylsalicylate in toluene (0,2M, 3.0 ml) to a solution of 4-(4-aminophenoxy)-2-{[4-(dimethylaminomethyl)piperidine-1-yl]carbylamine}pyridine (79 mg) and (+)-10-camphorsulfonic acid (49,7 mg) in ethanol (3.0 ml) at room temperature, the mixture is stirred over night. The reaction mixture is distributed between ethyl acetate and saturated aqueous sodium bicarbonate. The organic layer was washed with saturated aqueous sodium hydrogen carbonate and saturated saline solution in that order and dried over anhydrous sodium sulfate. The solvent is distilled off and the residue is purified column chromatography on silica gel (Fuji Silysia NH, eluent: ethyl acetate:heptane = 4:1), obtaining specified in the header connection (to 36.5 mg, 30%) as white powder.

Range1H-NMR (CDCl3) δ (ppm): of 1.10-1.20 (2H, m), 1,50-1,90 (3H, m), 2,10-of 2.15 (2H, m), of 2.21 (6H, c), 2,80-2,95 (2H, m), 3,71 (2H, c), 4,00-to 4.15 (2H, m), 6,53 (1H, DD, J=2,4, 5,6 Hz), 7,10-7,40 (7H, m), 7,60-of 7.70 (3H, m), of 8.04 (1H, d, J=5.6 Hz), 8,63 (1H, Sirs), 12,27 (1H, Sirs).

ESI-MS (m/z): 565[M+H]+.

Example of getting 188-1

4-(4-Amino-3-chlorophenoxy)-2-{[4-(dimethylaminomethyl)piperidine-1-yl]carbylamine}pyridine

2-Amino-4-(4-amino-3-chlorophenoxy)pyridine (100 mg) is dissolved in tetrahedr is a furan (2 ml) under nitrogen atmosphere. Add drop wise addition of triethylamine (amount of 0.118 ml) and phenylcarbamate (0,106 ml), cooling in a bath containing ice water. After stirring for 15 minutes at room temperature the solvent is distilled off under reduced pressure. To the resulting residue at room temperature under nitrogen atmosphere add a solution of dihydrochloride of 4-(dimethylaminomethyl)piperidine (456 mg) in N,N-dimethylformamide (4.0 ml) and triethylamine (0,591 ml), after which the mixture is stirred over night. The reaction mixture is distributed between ethyl acetate and water. The organic layer was washed with 1 N. aqueous sodium hydroxide solution and saturated saline solution in that order and dried over anhydrous sodium sulfate. The solvent is distilled off under reduced pressure and then the residue is purified column chromatography on silica gel (Fuji Silysia NH, eluent: ethyl acetate:heptane = 2:1, then ethyl acetate), obtaining mentioned in the title compound (122 mg, 71%) as a powder pale yellow color.

ESI-MS (m/z): 404[M+H]+.

Example of getting 188-2

4-(4-Aminophenoxy)-2-{[4-(dimethylaminomethyl)piperidine-1-yl]carbylamine}pyridine

4-(4-Amino-3-chlorophenoxy)-2-{[4-(dimethylaminomethyl)piperidine-1-yl]carbylamine}pyridine (122 mg) was dissolved in methanol (15 ml). Then add 10% palladium on coal (123 mg) and the mixture is stirred for 3 days in a hydrogen atmosphere. The catalyst hotfil throwaway and washed with methanol. The filtrate and washings are combined to a concentrated under reduced pressure and the resulting residue is dried under reduced pressure, obtaining mentioned in the title compound (79 mg, 71%) as a colourless oil.

ESI-MS (m/z): 370[M+H]+.

Example 189

4-[3-(Dimethylamino)azetidin-1-yl]piperidine-1-carboxylic acid [4-(3-fluoro-4-{3-[2-(4-forfinal)acetyl]touraid}phenoxy)pyridine-2-yl]amide

After adding 20% palladium hydroxide on coal (50 mg) to a solution of benzyl {4-[2-({4-[3-(dimethylamino)azetidin-1-yl]piperidine-1-carbonyl}amino)pyridine-4-yloxy]-2-forfinal}carbamate (135 mg) in tetrahydrofuran (10.0 ml) and the mixture is stirred for 8 hours at room temperature in a hydrogen atmosphere. The catalyst is filtered off and the filtrate is concentrated, leaving 3 ml of solvent to obtain crude 4-[3-(dimethylamino)azetidin-1-yl]piperidine-1-carboxylic acid [4-(4-amino-3-pertenece)pyridine-2-yl]amide (ESI-MS (m/z): 429 [M+H]+). To the crude product add ethanol (3.0 ml) and (1S)-(+)-10-camphorsulfonic acid (68,3 mg). After stirring at room temperature for 10 minutes add 2-(4-forfinal)acetilsalicilic (0,2M solution in toluene and 3.15 ml) and the mixture is stirred at room temperature. After 30 minutes, add 2-(4-forfinal)acetilsalicilic (0,2M solution in toluene, 4.26 deaths ml) and stirring is continued at room temperature is e for 3.5 hours. To the reaction solution was added ethyl acetate and saturated aqueous sodium hydrogen carbonate solution, whereupon the mixture is stirred at room temperature for 2 hours and then distribute. The aqueous layer was extracted with ethyl acetate, the organic layer is separated and washed with saturated saline solution. Then it is dried over anhydrous sodium sulfate and concentrated. The residue is purified column chromatography on silica gel (Fuji Silysia NH, eluent: ethyl acetate, then ethyl acetate:methanol = 10:1). The fractions containing the target compound concentrate. Add diethyl ether and hexane and the precipitate (41.3 mg) is filtered off. After removal of 12 mg of powder remaining 29.3 mg again purified column chromatography on silica gel (Fuji Silysia NH, eluent: ethyl acetate, then ethyl acetate:methanol = 10:1). The fractions containing the target compound are combined and concentrated. Add diethyl ether and hexane, after which the precipitate is filtered. Then it is dried in the air stream, receiving specified in the header connection (12,8 mg) as white powder.

1H-NMR Spectrum (CDCl3) δ (ppm): 1,24-of 1.35 (2H, m), 1,71 (2H, m), 2,11 (6H, c), and 2.26 (1H, m), 2,84 (3H, m), 3,06 (2H, m), 3,49 (2H, m), and 3.72 (2H, c), 3,88 (2H, m), 6,55 (1H, DD, J=2,4, 5,6 Hz)6,91 (2H, d, J=8,8 Hz), 7,11 (2H, m), 7,13-7,31 (3H, m), to 7.67 (1H, d, J=2.4 Hz), 8,07 (1H, d, J=5.6 Hz), 8,32 (1H, m)8,64 (1H, Sirs), 12,29 (1H, c).

ESI-MS (m/z): 624[M+H]+.

The example on the teachings 189-1

Tert-butyl 3-dimethylimidazolidin-1-carboxylate

After adding a 2M solution of dimethylamine in tetrahydrofuran (21,9 ml), acetic acid (1.73 ml) and 10% palladium on coal (2.15 g) to a solution of 1-Boc-azetidin-3-one (of 3.45 g) in methanol (175 ml) the mixture is stirred for 14 hours at room temperature in a hydrogen atmosphere. The catalyst is filtered off and the filtrate is concentrated under reduced pressure. The residue is distributed between ethyl acetate and saturated aqueous sodium bicarbonate. The combined organic layer is dried over anhydrous sodium sulfate. Then their focus, getting mentioned in the title compound (4,07 g, 101%) as a colourless oil.

Range1H-NMR (CDCl3) δ (ppm): USD 1.43 (9H, m), 2,17 (6H, c), a 3.01 (1H, m), with 3.79 (2H, m), 3,91 (2H, m).

Example of getting 189-2

Trihydrochloride N-[1-(1-benzylpiperidine-4-yl)azetidin-3-yl]-N,N-dimethylamine

tert-Butyl 3-dimethylimidazolidin-1-carboxylate (7,00 g) is stirred while cooling in a bath with ice, add triperoxonane acid (21,6 ml) and the mixture is stirred for 30 minutes in a bath with ice and then for 1.5 hours at room temperature. The reaction mixture was concentrated and receive crude DATEFORMAT 3-(dimethylamino)azetidine (ESI-MS (m/z): 101[M+H]+in the form of a brown oil. The obtained product is dissolved in dichloromethane (350 ml), was added 1-ensil-4-piperidone (of 6.49 ml) and the mixture is stirred for 10 minutes at room temperature. Then the mixture is cooled on ice, add triacetoxyborohydride sodium (11.1 g) and stirred at room temperature for 2 hours. The reaction mixture was concentrated. To the residue is added ethyl acetate (300 ml), saturated salt solution and potassium carbonate, stirred at room temperature for 20 minutes, after which the mixture is distributed. The aqueous layer was extracted with a mixture of ethyl acetate:tetrahydrofuran = 1:1. The organic layers are combined, dried and added 4 n hydrochloric acid in ethyl acetate (26,3 ml). The mixture of concentrate and get the crude specified in the title compound (14.1 g) as colorless crystals.

ESI-MS (m/z): 274[M+H]+.

Example of getting 189-3

Trihydrochloride N,N-dimethyl-N-[1-(piperidine-4-yl)azetidin-3-yl]amine

After adding 10% palladium on coal (5.0 g) to a solution of crude trihydrochloride N-[1-(1-benzylpiperidine-4-yl)azetidin-3-yl]-N,N-dimethylamine (14.1 g) in a mixture of 2-propanol (380 ml) - water (380 ml), the mixture is stirred for 12 hours at room temperature in a hydrogen atmosphere. Then the catalyst is filtered off. The filtrate is concentrated under reduced pressure, obtaining the crude specified in the title compound (10.7 g) as colorless crystals.

ESI-MS (m/z): 184[M+H]+.

Example of getting 189-4

Benzyl {4-[2-({4-[3-(dimethylamino)azetidin-1-yl]piperidine-1-Carboni is}amino)pyridine-4-yloxy]-2-forfinal}carbamate

After adding triethylamine (0,169 ml) and phenylcarbamate (of 0.133 ml) to a solution of benzyl [4-(2-aminopyridine-4-yloxy)-2-forfinal]carbamate (150 mg) in tetrahydrofuran (6,64 ml) the mixture is stirred for 23 hours at room temperature in a nitrogen atmosphere. The reaction mixture was concentrated under reduced pressure. After adding to the residue N,N-dimethylformamide (1.5 ml), trihydrochloride dimethyl-[1-(piperidine-4-yl)azetidin-3-yl]amine (498 mg) and triethylamine (0,200 ml) the mixture is stirred for 12 hours at room temperature. To the reaction mixture are added ethyl acetate (30 ml) and 1 N. aqueous sodium hydroxide solution (10 ml), then stirred at room temperature for 1 hour. Add saturated salt solution and the mixture extracted with ethyl acetate. The aqueous layer was extracted with ethyl acetate. The organic layers are combined and washed with 1 N. aqueous sodium hydroxide solution and saturated saline solution in this order, then dried over anhydrous sodium sulfate. The dried organic layer is concentrated and the residue purified column chromatography on silica gel (Fuji Silysia NH, eluent: ethyl acetate, then ethyl acetate:methanol = 19:1). The fractions containing the target compound, concentrate, and get mentioned in the title compound (118 mg, 49,3%) as a solid pale yellow color.

Range1H-NMR (CDCl 3) δ (ppm): 1,26-of 1.35 (2H, m)of 1.73 (2H, m), 2,12 (6H, c in), 2.25 (1H, m), and 2.83 (3H, m), 3,05 (2H, m), 3,49 (2H, m), 3,88 (2H, m), 5,23 (2H, c), of 6.50 (1H, DD, J=2,4, 6,0 Hz), 6,85-6,91 (3H, m), 7.23 percent-7,26 (2H, m), 7,35-7,42 (4H, m), to 7.61 (1H, d, J=2.4 Hz), of 8.04 (1H, d, J=6.0 Hz), 8,14 (1H, Sirs).

ESI-MS (m/z): 563[M+H]+.

Example 190

2-{[4-(4-Hydroxypiperidine-1-yl)piperidine-1-yl]carbylamine}―4-(4-{3-[2-(4-forfinal)acetyl]touraid}phenoxy)pyridine

After adding a solution of 2-(4-forfinal)acetylsalicylate in toluene (0,25M, 3.0 ml) to a solution of 4-(4-aminophenoxy)-2-{[4-(4-hydroxypiperidine-1-yl)piperidine-1-yl]carbylamine}pyridine (214 mg) and (+)-10-camphorsulfonic acid (105 mg) in ethanol (4.0 ml) at room temperature, the mixture is stirred for 4 hours. The reaction mixture is distributed between ethyl acetate and saturated aqueous sodium bicarbonate. The organic layer was washed with saturated aqueous sodium hydrogen carbonate and saturated saline, then dried over anhydrous sodium sulfate. The solvent is distilled off and the residue is purified column chromatography on silica gel (Fuji Silysia NH, eluent: ethyl acetate:methanol = 100:0 to 97:3), receiving specified in the header of the connection (or 58.6 mg, 19%) as white powder.

Range1H-NMR (CDCl3) δ (ppm): 1,40-2,00 (8H, m), 2,32 (2H, m), of 2.51 (1H, m), of 2,75 2,95 (4H, m), 3,60-of 3.80 (3H, m), 4,05-4,20 (2H, m), is 6.54 (1H, DD, J=2,4, 5,6 Hz), 7,10-7,40 (7H, m), 7,63 (1H, d, J=2.4 Hz), to 7.67-of 7.70 (2H, m)of 8.04 (1H, d, J=5.6 Hz), and 8.50 (1H, Shi is .c), of 12.26 (1H, Sirs).

ESI-MS (m/z): 607[M+H]+.

Example of getting 190-1

2-{[4-(4-Hydroxypiperidine-1-yl)piperidine-1-yl]carbylamine}-4-(4-nitrophenoxy)pyridine

2-Amino-4-(4-nitrophenoxy)pyridine (116 mg) was dissolved in tetrahydrofuran (2.5 ml) under nitrogen atmosphere. Then add dropwise a triethylamine (0,175 ml) and phenylcarbamate (of) 0.157 ml), cooling in a bath containing ice water. After stirring for 30 minutes at room temperature the solvent is distilled off under reduced pressure. To the resulting residue at room temperature under nitrogen atmosphere add a solution of 4-(4-hydroxypiperidine-1-yl)piperidine (500 mg) in N,N-dimethylformamide (5.0 ml) and the mixture is stirred over night. The reaction mixture is distributed between ethyl acetate and water. The organic layer was washed with 1 N. aqueous sodium hydroxide solution and saturated saline, then dried over anhydrous sodium sulfate. The solvent is distilled off under reduced pressure and then the residue is purified column chromatography on silica gel (Fuji Silysia NH, eluent: ethyl acetate:methanol = 100:0 to 97:3), getting mentioned in the title compound (243 mg) in the form of oil pale yellow color.

1H-NMR Spectrum (CDCl3) δ (ppm): 1,40-2,00 (8H, m), 2,33 (2H, m), 2,52 (1H, m), 2,75-3,00 (4H, m), 3,71 (1H, m), 4,00-4,20 (2H, m), only 6.64 (1H, DD, J=2,4, 5,6 Hz), 7,15-7,30 (3H, m), of 7.75 (1H, d, J=2.4 Hz), 8,16 (1H, d, J=5.6 Hz), 8,25-8,30 (2H, m).

Use the get 190-2

4-(4-Aminophenoxy)-2-{[4-(4-hydroxypiperidine-1-yl)piperidine-1-yl]carbylamine}pyridine

2-{[4-(4-Hydroxypiperidine-1-yl)piperidine-1-yl]carbylamine}-4-(4-nitrophenoxy)pyridine (243 mg) was dissolved in tetrahydrofuran (25 ml). Then add 20% palladium hydroxide on coal (140 mg) and the mixture is stirred overnight in a hydrogen atmosphere. The catalyst is filtered off and washed with tetrahydrofuran. The filtrate and washings are then combined and concentrated under reduced pressure, after which the resulting residue is dried under reduced pressure, obtaining mentioned in the title compound (214 mg) in the form of a powder pale yellow color.

ESI-MS (m/z): 412 [M+H]+.

Example 191

4-(4-{3-[2-(4-Forfinal)acetyl]touraid}phenoxy)-2-{[4-(1-methylpiperazin-4-yl)piperidine-1-yl]carbylamine}pyridine

After adding a solution of 2-(4-forfinal)acetylsalicylate in toluene (0.25 M, 3.0 ml) to a solution of 4-(4-aminophenoxy)-2-{[4-(1-methylpiperazin-4-yl)piperidine-1-yl]carbylamine}pyridine (149 mg) and (+)-10-camphorsulfonic acid (152 mg) in ethanol (4.0 ml) at room temperature, the mixture is stirred for 3 hours. The reaction mixture is distributed between ethyl acetate and saturated aqueous sodium bicarbonate. The organic layer was washed with saturated aqueous sodium hydrogen carbonate and saturated saline, then dried over anhydrous with what LifeCam sodium. The solvent is then distilled off and the residue is purified column chromatography on silica gel (Fuji Silysia NH, eluent: ethyl acetate:methanol = 98:2 to 97:3), receiving specified in the header connection (88,2 mg, 40%) as white powder.

Range1H-NMR (CDCl3) δ (ppm): 1,40-2,00 (5H, m), of 2.34 (3H, c), 2,40-of 3.00 (10H, m), 3,71 (2H, c), 4,05-4,20 (2H, m), is 6.54 (1H, DD, J=2,4, 5,6 Hz), 7,10-7,40 (7H, m), 7,63 (1H, d, J=2.4 Hz), to 7.67-of 7.70 (2H, m), of 8.04 (1H, d, J=5.6 Hz), of 8.47 (1H, Sirs), of 12.26 (1H, Sirs).

ESI-MS (m/z): 606[M+H]+.

Example of getting 191-1

2-{[4-(1-Methylpiperazin-4-yl)piperidine-1-yl]carbylamine}-4-(4-nitrophenoxy)pyridine

2-Amino-4-(4-nitrophenoxy)pyridine (116 mg) was dissolved in tetrahydrofuran (2.5 ml) under nitrogen atmosphere. Then add dropwise a triethylamine (0,175 ml) and phenylcarbamate (of) 0.157 ml), cooling in a bath containing ice water. After stirring for 30 minutes at room temperature the solvent is distilled off under reduced pressure. To the resulting residue at room temperature under nitrogen atmosphere add a solution of 4-(1-methylpiperazin-4-yl)piperidine (500 mg) in N,N-dimethylformamide (5.0 ml) and the mixture is stirred over night. The reaction mixture is distributed between ethyl acetate and water. The organic layer was washed with 1 N. aqueous sodium hydroxide solution and saturated saline, then dried over anhydrous sodium sulfate. The solvent is distilled off under reduced giving the situation and then the resulting residue is purified column chromatography on silica gel (Fuji Silysia NH, eluent: ethyl acetate:methanol = 100:0 to 97:3), getting mentioned in the title compound (163 mg, 74%) as oil pale yellow color.

Range1H-NMR (CDCl3) δ (ppm): 1,40-2,00 (5H, m), 2,31 (3H, c), 2,40-of 3.00 (10H, m), 4,00-4,20 (2H, m), only 6.64 (1H, DD, J=2,4, 5,6 Hz), 7,15-7,30 (3H, m), of 7.75 (1H, d, J=2.4 Hz), 8,15 (1H, d, J=5.6 Hz), 8,25-8,30 (2H, m).

Example of getting 191-2

4-(4-Aminophenoxy)-2-{[4-(1-methylpiperazin-4-yl)piperidine-1-yl]carbylamine}pyridine

2-{[4-(1-Methylpiperazin-4-yl)piperidine-1-yl]carbylamine}-4-(4-nitrophenoxy)pyridine (163 mg) was dissolved in tetrahydrofuran (20 ml). After adding 20% palladium hydroxide on coal (104 mg) the mixture is stirred overnight in a hydrogen atmosphere. The catalyst is filtered off and washed with tetrahydrofuran. The filtrate and washings are combined and concentrated under reduced pressure, after which the resulting residue is dried under reduced pressure, obtaining mentioned in the title compound (149 mg, 98%) as a powder pale yellow color.

ESI-MS (m/z): 411[M+H]+.

Example 192

4-(2-Fluoro-4-{3-[2-(4-forfinal)acetyl]touraid}phenoxy)-6-{[4-(1-methylpiperazin-4-yl)piperidine-1-yl]carbylamine}pyrimidine

After adding a solution of 2-(4-forfinal)acetylsalicylate in toluene (0,25M, 2.0 ml) to a solution of 4-(4-amino-2-pertenece)-6-{[4-(1-methylpiperazin-4-yl)piperidine-1-yl]carbylamine}pyrimidine (98 mg) and (+)-10-camphorsulfonic acid (79 mg) in ethanol (2.0 ml) is room temperature and the mixture is stirred for 3.5 hours. The reaction mixture is distributed between ethyl acetate and saturated aqueous sodium bicarbonate. The organic layer was washed with saturated aqueous sodium hydrogen carbonate and saturated saline, then dried over anhydrous sodium sulfate. The solvent is then distilled off and the residue is purified column chromatography on silica gel (Fuji Silysia NH, eluent: ethyl acetate, then ethyl acetate:methanol = 97:3), receiving specified in the header connection (to 65.2 mg, 46%) as white powder.

Range1H-NMR (CDCl3) δ (ppm): 1,40-2,00 (5H, m), is 2.30 (3H, c), 2,40-of 3.00 (10H, m), 3,71 (2H, c), 4,00-4,20 (2H, m), 7,10-7,40 (7H, m), a 7.62 (1H, d, J=0.8 Hz), 7,86 (1H, DD, J=2,4, and 11.6 Hz), with 8.33 (1H, d, J=0.8 Hz), 8,64 (1H, Sirs), 12,40 (1H, Sirs).

ESI-MS (m/z): 625[M+H]+.

Example of getting 192-1

4-(2-Fluoro-4-nitrophenoxy)-6-{[4-(1-methylpiperazin-4-yl)piperidine-1-yl]carbylamine}pyrimidine

4-Amino-6-(2-fluoro-4-nitrophenoxy)pyrimidine (100 mg) dissolved in tetrahydrofuran (2 ml) under nitrogen atmosphere. Add drop wise addition of triethylamine (0,139 ml) and phenylcarbamate (0,125 ml), cooling in a bath containing ice water. After stirring for 15 minutes at room temperature the solvent is distilled off under reduced pressure. To the resulting residue at room temperature under nitrogen atmosphere add a solution of 4-(1-methylpiperazin-4-yl)piperidine (440 mg) in N,N-dimethylformamide (4.0 ml) and the mixture per mesilat within 2 hours. The reaction mixture is distributed between ethyl acetate and water. The organic layer was washed with 1 N. aqueous sodium hydroxide solution and saturated saline, then dried over anhydrous sodium sulfate. The solvent is distilled off under reduced pressure and then the residue is purified column chromatography on silica gel (Fuji Silysia NH, eluent: ethyl acetate, then ethyl acetate:methanol = 97:3), getting mentioned in the title compound (104 mg, 57%) as oil pale yellow color.

Range1H-NMR (CDCl3) δ (ppm): 1,40-2,00 (5H, m), of 2.34 (3H, c), 2,40-of 3.00 (10H, m), 4,00-4,20 (2H, m), 7,35-7,45 (2H, m), 7,73 (1H, d, J=0.8 Hz), 8.07-a of 8.15 (2H, m), 8,32 (1H, d, J=0.8 Hz).

Example of getting 192-2

4-(4-Amino-2-pertenece)-6-{[4-(1-methylpiperazin-4-yl)piperidine-1-yl]carbylamine}pyrimidine

4-(2-Fluoro-4-nitrophenoxy)-6-{[4-(1-methylpiperazin-4-yl)piperidine-1-yl]carbylamine}pyrimidine (104 mg) was dissolved in tetrahydrofuran (15 ml). After adding 20% palladium hydroxide on coal (70 mg) the mixture is stirred overnight in a hydrogen atmosphere. The catalyst is filtered off and washed with tetrahydrofuran. The filtrate and washings are combined and concentrated under reduced pressure, after which the resulting residue is dried under reduced pressure, obtaining mentioned in the title compound (98 mg, quantitative yield) as oil pale yellow color.

ESI-MS (m/z): 430[M+H]+.

Example 193

4-(2-what Thor-4-{3-[2-(4-forfinal)acetyl]touraid}phenoxy)-6-{[4-(1-methylpiperidin-4-yl)piperazine-1-yl]carbylamine}pyrimidine

After adding a solution of 2-(4-forfinal)acetylsalicylate in toluene (0,25M, 2.5 ml) to a solution of 4-(4-amino-2-pertenece)-6-{[4-(1-methylpiperidin-4-yl)piperazine-1-yl]carbylamine}pyrimidine (134 mg) and (+)-10-camphorsulfonic acid (109 mg) in ethanol (3.0 ml) at room temperature, the mixture is stirred for 3.5 hours. The reaction mixture is distributed between ethyl acetate and saturated aqueous sodium bicarbonate. The organic layer was washed with saturated aqueous sodium hydrogen carbonate and saturated saline solution in that order and dried over anhydrous sodium sulfate. The solvent is distilled off and the residue is purified column chromatography on silica gel (Fuji Silysia NH, eluent: ethyl acetate, then ethyl acetate:methanol = 98:2). The fractions containing the target compound, concentrate, and get mentioned in the title compound (60,7 mg, 31%) as white powder.

Range1H-NMR (CDCl3) δ (ppm): 1,50-2,10 (6H, m), 2,20-2,40 (4H, m), 2,55-to 2.65 (4H, m), 2,90-3,10 (2H, m), 3,50-3,60 (4H, m), 3,71 (2H, c), 7,10-7,40 (7H, m), 7,63 (1H, d, J=0.8 Hz), 7,87 (1H, DD, J=2,4, and 11.6 Hz), with 8.33 (1H, d, J=0.8 Hz), 8,44 (1H, Sirs), 12,38 (1H, Sirs).

ESI-MS (m/z): 625[M+H]+.

Example of getting 193-1

4-(2-Fluoro-4-nitrophenoxy)-6-{[4-(1-methylpiperidin-4-yl)piperazine-1-yl]carbylamine}pyrimidine

4-Amino-6-(2-fluoro-4-nitrophenoxy)pyrimidine (100 mg) dissolved in tetrahydrofuran (2 ml) under nitrogen atmosphere. The ZAT is added drop wise addition of triethylamine (0,139 ml) and phenylcarbamate (0,125 ml), cooling in a bath containing ice water. After stirring for 15 minutes at room temperature the solvent is distilled off under reduced pressure. To the resulting residue at room temperature under nitrogen atmosphere add a solution of 4-(1-methylpiperidin-4-yl)piperazine (440 mg) in N,N-dimethylformamide (4.0 ml) and the mixture is stirred for 2 hours. Then the reaction mixture is distributed between ethyl acetate and water. The organic layer was washed with 1 N. aqueous sodium hydroxide solution and saturated saline solution in that order and dried over anhydrous sodium sulfate. The solvent is distilled off under reduced pressure and then the residue is purified column chromatography on silica gel (Fuji Silysia NH, eluent: ethyl acetate, then ethyl acetate:methanol = 97:3), getting mentioned in the title compound (145 mg, 79%) as oil pale yellow color.

Range1H-NMR (CDCl3) δ (ppm): 1,60-2,00 (6H, m), 2,20-of 2.30 (1H, m), 2,28 (3H, c), 2,55-to 2.65 (4H, m), 2,80-3,00 (2H, m), 3,40-of 3.60 (4H, m), 7,35-7,45 (2H, m), 7,73 (1H, d, J=0.8 Hz), 8.07-a of 8.15 (2H, m), 8,32 (1H, d, J=0,8 Hz).

Example of getting 193-2

4-(4-Amino-2-pertenece)-6-{[4-(1-methylpiperidin-4-yl)piperazine-1-yl]carbylamine}pyrimidine

4-(2-Fluoro-4-nitrophenoxy)-6-{[4-(1-methylpiperidin-4-yl)piperazine-1-yl]carbylamine}pyrimidine (145 mg) was dissolved in tetrahydrofuran (20 ml). After adding 20% palladium hydroxide on coal (100 mg) the mixture paramesh what happens during the night in an atmosphere of hydrogen. The catalyst is filtered off and washed with tetrahydrofuran. The filtrate and washings are combined and concentrated under reduced pressure, after which the resulting residue is dried under reduced pressure, obtaining mentioned in the title compound (134 mg, 99%) as oil pale yellow color.

ESI-MS (m/z): 430[M+H]+.

Example 194

1-[1-(2-Dimethylaminoethyl)piperidine-4-yl]-3-[4-(4-{3-[2-(4-forfinal)acetyl]touraid}phenoxy)pyridine-2-yl]-1-metalmachine

After addition of (1S)-(+)-10-camphorsulfonic acid (119 mg) to a solution of 3-[4-(4-aminophenoxy)pyridine-2-yl]-1-[1-(2-dimethylaminoethyl)piperidine-4-yl]-1-metalmachine (121 mg) in ethanol (2.0 ml), the mixture is stirred for 10 minutes at room temperature. Then add 2-(4-forfinal)acetilsalicilic (2,34 ml, 0,25M solution in toluene) and the mixture is stirred at room temperature for 50 minutes. Then the reaction mixture is distributed between ethyl acetate and saturated aqueous sodium bicarbonate. The organic layer is dried over anhydrous sodium sulfate and concentrated. The residue is purified column chromatography on silica gel (Fuji Silysia NH, ethyl acetate, then ethyl acetate:methanol = 20:1 to 10:1). The fractions containing the target compound are combined and concentrated. The residue is purified by LC-MS (eluent: system acetonitrile-water-triperoxonane acid). The fractions containing the target is Obedinenie, concentrated and to the residue is added saturated aqueous solution of sodium bicarbonate. The mixture is extracted with ethyl acetate, the organic layer was washed with saturated saline and dried over anhydrous sodium sulfate. Then his focus, getting listed at the beginning of the connection (to 26.3 mg, 14.8 per cent) in the form of white powder.

Range1H-NMR (CDCl3) δ (ppm): of 1.64 (2H, m), of 1.78 (2H, m), 2,10 (2H, m), 2,28 (6H, c), 2,47 (4H, m), is 2.88 (3H, c), 3,10 (2H, m), 3,70 (2H, c), of 4.16 (1H, m), 6,55 (1H, DD, J=2,4, 5,6 Hz), 7,08-7,16 (4H, m), 7,20 (1H, Sirs), 7,25-7,31 (2H, m), 7,66-of 7.69 (2H, m), of 8.06 (1H, d, J=5.6 Hz), 8,82 (1H, Sirs), to 12.28 (1H, c).

ESI-MS (m/z): 608[M+H]+.

Example of getting 194-1

1-[1-(2-Dimethylaminoethyl)piperidine-4-yl]-1-methyl-3-[4-(4-nitrophenoxy)pyridine-2-yl]urea

After adding triethylamine (0,209 ml) and phenylcarbamate (of) 0.157 ml) to a solution of 4-(4-nitrophenoxy)pyridine-2-ylamine (116 mg) in tetrahydrofuran (5.0 ml) at room temperature, the mixture is stirred for 30 minutes at room temperature in a nitrogen atmosphere. Then the reaction mixture was concentrated. To the residue is added N,N-dimethylformamide (2.0 ml) and N-[1-(2-dimethylaminoethyl)piperidine-4-yl]-N-methylamine (463 mg) and stirred at room temperature for 6 hours. To the reaction mixture are added ethyl acetate and 1 N. aqueous sodium hydroxide solution and stirred for 15 minutes, after which the mixture is distributed. The aqueous layer EC is tracerout with ethyl acetate. The organic layers are combined, washed with saturated saline and dried over anhydrous sodium sulfate. After concentration the residue is purified column chromatography on silica gel (Fuji Silysia NH, eluent: ethyl acetate, then ethyl acetate:methanol = 20:1 to 10:1). The fractions containing the target compound, concentrate, and get mentioned in the title compound (186 mg, 84,1%) in the form of oil pale yellow color.

Range1H-NMR (CDCl3) δ (ppm): of 1.65 (2H, m)to 1.79 (2H, m), 2,10 (2H, m), of 2.25 (6H, c), 2,40-of 2.50 (4H, m), 2,90 (3H, c), a 3.01 (2H, m), is 4.15 (1H, m), of 6.65 (1H, DD, J=2,4, 5,6 Hz), 7,18 (2H, d, J=9,2 Hz), 7,25 (1H, Sirs), 7,80 (1H, d, J=2.4 Hz), 8,17 (1H, d, J=5.6 Hz), of 8.27 (2H, d, J=9,2 Hz).

ESI-MS (m/z): 443[M+H]+.

Example of getting 194-2

3-[4-(4-Aminophenoxy)pyridine-2-yl]-1-[1-(2-dimethylaminoethyl)piperidine-4-yl]-1-metalmachine

After adding 20% palladium hydroxide on coal (50 mg) to a solution of 1-[1-(2-dimethylaminoethyl)piperidine-4-yl]-1-methyl-3-[4-(4-nitrophenoxy)pyridine-2-yl]urea (186 mg) in tetrahydrofuran (5.0 ml) and the mixture is stirred for 12 hours at room temperature in a hydrogen atmosphere. The catalyst is filtered off. The filtrate is concentrated, getting mentioned in the title compound (121 mg, 69,8%) in the form of oil pale yellow color.

Range1H-NMR (CDCl3) δ (ppm): of 1.64 (2H, m), of 1.78 (2H, m), 2,10 (2H, m), and 2.26 (6H, c), 2,42 is 2.51 (4H, m), 2,87 (3H, c), 2,97 totaling 3.04 (2H, m), 4,18 (1H, m), 6.48 in (1H, DD, J=2,4, 6,0 Hz), 6,70 (2H, d, J=8,8 Hz), 6.90 to (2, d, J=8,8 Hz), 7,21 (1H, Sirs), a 7.62 (1H, d, J=2.4 Hz), to 7.99 (1H, d, J=6.0 Hz).

ESI-MS (m/z): 413[M+H]+.

Example 195

4-[3-(Dimethylamino)azetidin-1-yl]piperidine-1-carboxylic acid [4-(4-{3-[2-(4-forfinal)acetyl]touraid}phenoxy)pyridine-2-yl]amide

After addition of (1S)-(+)-10-camphorsulfonic acid (90,7 mg) to a solution of 4-[3-(dimethylamino)azetidin-1-yl]piperidine-1-carboxylic acid [4-(4-aminophenoxy)pyridine-2-yl]amide (from 91.5 mg) in ethanol (2.0 ml), the mixture is stirred for 10 minutes at room temperature. Then add 2-(4-forfinal)acetilsalicilic (1,28 ml, 0,25M solution in toluene) and stirred at room temperature for 50 minutes. The reaction mixture is distributed between ethyl acetate and saturated aqueous sodium bicarbonate. The organic layer is dried over anhydrous sodium sulfate and concentrated. The residue is purified column chromatography on silica gel (Fuji Silysia NH, ethyl acetate, then ethyl acetate:methanol = 20:1 to 10:1). Fractions containing the target compound are pooled and concentrated. The residue is then purified by LC-MS (eluent: system acetonitrile-water-triperoxonane acid). The fractions containing the target compound are combined and concentrated, then the residue is added saturated aqueous solution of sodium bicarbonate. The mixture is extracted with ethyl acetate, the organic layer was washed with saturated saline races is a thief and dried over anhydrous sodium sulfate. It is then concentrated, the precipitate is suspended in a mixture of diethyl ether-hexane and filtered. The filtered solid is washed with diethyl ether. Then it is dried by aspiration, getting mentioned in the title compound (14,2 mg, 10.5 per cent) in the form of white powder.

Range1H-NMR (CDCl3) δ (ppm): 1,31 (2H, m), 1,72 (2H, m)of 2.16 (6H, c), of 2.33 (1H, m)to 2.94 (3H, m), 3.04 from (2H, m), of 3.56 (2H, m), 3,71 (2H, c), 3,90 (2H, m), 6,53 (1H, DD, J=2,4, 6,0 Hz), 7,12 (4H, m), 7,26-7,31 (3H, m), 7,63-of 7.69 (3H, m), of 8.04 (1H, d, J=6.0 Hz), 8,55 (1H, c), of 12.26 (1H, c).

ESI-MS (m/z): 606[M+H]+, 628[M+Na]+.

Example of getting 195-1

4-[3-(Dimethylamino)azetidin-1-yl]piperidine-1-carboxylic acid [4-(4-nitrophenoxy)pyridine-2-yl]amide

After adding triethylamine (0,209 ml) and phenylcarbamate (of) 0.157 ml) to a solution of 4-(4-nitrophenoxy)pyridine-2-ylamine (116 mg) in tetrahydrofuran (5.0 ml) at room temperature, the mixture is stirred at the same temperature under nitrogen atmosphere for 30 minutes. Then the reaction mixture was concentrated. To the residue add triethylamine (0,697 ml), trihydrochloride N,N-dimethyl-N-[1-(piperidine-4-yl)azetidin-3-yl]amine (5.0 ml, 0,5M solution in N,N-dimethylformamide) and water (0.2 ml), then stirred at room temperature for 6 hours. To the reaction mixture are added ethyl acetate and 1 N. aqueous sodium hydroxide solution, stirred for 15 minutes, after which the mixture is distributed. The aqueous layer EC is tracerout with ethyl acetate. The organic layers are combined, washed with saturated saline and dried over anhydrous sodium sulfate. They are then concentrated and the residue purified column chromatography on silica gel (Fuji Silysia NH, eluent: ethyl acetate, then ethyl acetate:methanol = 20:1 to 10:1). The fractions containing the target compound, concentrate, and get mentioned in the title compound (112 mg, 50.9 per cent) in the form of oil pale yellow color.

Range1H-NMR (CDCl3) δ (ppm): 1,32 (2H, m), 1,71-to 1.77 (2H, m), 2,12 (6H, c), and 2.27 (1H, m), 2,84 (3H, m), of 3.07 (2H, m), 3,48-of 3.53 (2H, m), 3,85-3,91 (2H, m), 6,40 (1H, DD, J=2,0, 5.6 Hz), to 7.09 (1H, m), 7,18 (2H, d, J=9,2 Hz), 7,74 (1H, d, J=2.0 Hz), 8,15 (1H, d, J=5.6 Hz), of 8.27 (2H, d, J=9,2 Hz).

ESI-MS (m/z): 441[M+H]+.

Example of getting 195-2

4-[3-(Dimethylamino)azetidin-1-yl]piperidine-1-carboxylic acid [4-(4-aminophenoxy)pyridine-2-yl]amide

After adding 20% palladium hydroxide on coal (50 mg) to a solution of 4-[3-(dimethylamino)azetidin-1-yl]piperidine-1-carboxylic acid [4-(4-nitrophenoxy)pyridine-2-yl]amide (112 mg) in tetrahydrofuran (5.0 ml) and the mixture is stirred for 12 hours at room temperature in a hydrogen atmosphere. The catalyst is filtered off. The filtrate is concentrated and receiving specified in the header of the connection (from 91.5 mg, 87.8 per cent) in the form of oil pale yellow color.

Range1H-NMR (CDCl3) δ (ppm): 1,30 (2H, m), 1.70 to of 1.78 (2H, m), 2,12 (6H, c), and 2.26 (1H, m), 2,82-2,87 (3H, m), to 3.02 (2H, m), 3,48-3,55 (2H, m), 3,90 (2H, m), 6,47 (1H, is d, J=2,4, 5,6 Hz), 6,69 (2H, d, J=8,8 Hz), 6.89 in (2H, d, J=8,8 Hz), 7,40 (1H, Sirs), 7,55 (1H, m), of 7.96 (1H, d, J=5.6 Hz).

ESI-MS (m/z): 411[M+H]+.

Example 196

4-(1-Methylisatin-3-yl)piperazine-1-carboxylic acid [6-(2-fluoro-4-{3-[2-(4-forfinal)acetyl]touraid}phenoxy)pyrimidine-4-yl]amide

After addition of (1S)-(+)-10-camphorsulfonic acid (29,4 mg) to a solution of 4-(1-methylisatin-3-yl)piperazine-1-carboxylic acid [6-(4-amino-2-pertenece)pyrimidine-4-yl]amide (31.8 mg) in ethanol (1.5 ml), the mixture is stirred for 10 minutes at room temperature. Add a solution of 2-(4-forfinal)acetylsalicylate in toluene (0,25M, 0,634 ml) and stirred at room temperature for 30 minutes. The reaction mixture was partitioned between saturated aqueous sodium bicarbonate and ethyl acetate. The organic layer was washed with saturated saline and dried over anhydrous sodium sulfate. It is then concentrated and the residue purified by LC-MS (eluent: system acetonitrile-water-triperoxonane acid). The fractions containing the target compound, concentrate, and to the residue is added saturated aqueous solution of sodium bicarbonate. The mixture is then extracted with ethyl acetate. The organic layer was washed with saturated saline and dried over anhydrous sodium sulfate. The dried organic layer is concentrated and receiving specified in the title compound (8.0 mg, 1.9 per cent) in the form of white powder.

Range1H-NMR (CDCl3) δ (ppm): at 2.36 (4H, m), 2,43 (3H, c), 3,03 (3H, m), 3,55 (4H, m), 3,62 (2H, m), 3,71 (2H, c), 7,12 (2H, m), 7,21 (1H, m), 7,26-7,30 (2H, m), 7,34-7,39 (2H, m), 7,63 (1H, d, J=0.8 Hz), 7,86 (1H, DD, J=2,4, 11.2 Hz), with 8.33 (1H, d, J=0.8 Hz), 8,59 (1H, Sirs), KZT 12.39 (1H, c).

ESI-MS (m/z): 597[M+H]+.

Example of getting 196-1

Trihydrochloride 1-(1-methylisatin-3-yl)piperazine

After addition of 1-Boc-azetidin-3-one (495 mg) and acetic acid (of 0.182 ml) to a solution of 1-benzylpiperazine (0,500 ml) in methanol (25 ml), the mixture is stirred for 5 minutes at room temperature. Then add 10% palladium on coal (308 mg) and the mixture is stirred for 15 hours at room temperature in a hydrogen atmosphere. Then the catalyst is filtered off. The residue is distributed between ethyl acetate and saturated aqueous sodium bicarbonate. The organic layer was washed with saturated saline and then dried over anhydrous sodium sulfate. The dried organic layer is concentrated, obtaining the crude 4-benzyl-1-(1-Boc-azetidin-3-yl)piperazine (ESI-MS (m/z): 332[M+H]+). It is dissolved in tetrahydrofuran (10 ml). Then add the aluminum lithium hydride (219 mg), stirring the mixture in a bath with ice. After stirring for 15 minutes in a bath with ice in a nitrogen atmosphere and within 15 minutes at room temperature, the mixture is heated under reflux for 3.5 hours at 100°C. the Reaction see what camping is cooled in a bath with ice. Add water (0,22 ml), 5 N. aqueous sodium hydroxide solution (0,22 ml) and water (1.1 ml), after which the mixture is stirred in a bath with ice for 1 hour. The insoluble matter is filtered off. To the filtrate is added 4 n hydrochloric acid in ethyl acetate (2,17 ml) and the mixture is concentrated, obtaining the crude trihydrochloride 4-benzyl-1-(1-methylisatin-3-yl)piperazine (ESI-MS (m/z): 246[M+H]+). It is dissolved in water (25 ml) and 2-propanol (25 ml). After adding 10% palladium on coal (615 mg) the mixture is stirred for 12 hours at room temperature in a hydrogen atmosphere. The catalyst is filtered off. The filtrate is concentrated and receiving untreated specified in the title compound (382 mg) as a solid white color.

ESI-MS (m/z): 156[M+H]+.

Example of getting 196-2

4-(1-Methylisatin-3-yl)piperazine-1-carboxylic acid [6-(2-fluoro-4-nitrophenoxy)pyrimidine-4-yl]amide

After adding triethylamine (0,167 ml) and phenylcarbamate (0,126 ml) to a solution of 6-(2-fluoro-4-nitrophenoxy)pyrimidine-4-ylamine (100 mg) in tetrahydrofuran (5.0 ml), the mixture is stirred for 30 minutes at room temperature. The reaction mixture was concentrated, then added N,N-dimethylformamide (3.0 ml), trihydrochloride 1-(1-methylisatin-3-yl)piperazine (382 mg), triethylamine (0,669 ml) and water (0,30 ml) and the mixture is stirred at room temperature in 2,5 hours. To the reaction mixture are added ethyl acetate and 1 N. aqueous sodium hydroxide solution, and then stirred at room temperature for 20 minutes. The mixture is then extracted with ethyl acetate. The organic layer was washed with saturated saline and dried over anhydrous sodium sulfate. Then the dried organic layer is concentrated and the residue purified column chromatography on silica gel (Fuji Silysia NH, eluent: ethyl acetate ethyl acetate:methanol = 20:1 to 10:1). The fractions containing the target compound, concentrate, and get mentioned in the title compound (69,1 mg, 40,0%) as amorphous yellow substance.

Range1H-NMR (CDCl3) δ (ppm): 2,34-of 2.38 (7H, m), 2.91 in-to 3.02 (3H, m), 3,51-to 3.58 (6H, m), 7,42 (1H, m), 7,51 (1H, Sirs), 7,73 (1H, d, J=1.2 Hz), 8,11 (2H, m), 8,32 (1H, d, J=1.2 Hz).

ESI-MS (m/z): 432[M+H]+.

Example of getting 196-3

4-(1-Methylisatin-3-yl)piperazine-1-carboxylic acid [6-(4-amino-2-pertenece)pyrimidine-4-yl]amide

After adding 20% palladium hydroxide (150 mg) to a solution of 4-(1-methylisatin-3-yl)piperazine-1-carboxylic acid [6-(2-fluoro-4-nitrophenoxy)pyrimidine-4-yl]amide (69,1 mg) in tetrahydrofuran the mixture is stirred for 7 hours at room temperature in a hydrogen atmosphere. Then the catalyst is filtered off. The filtrate is concentrated, getting mentioned in the title compound (31.8 mg, 64,2%) as a yellow oil.

ESI-MS (m/z): 402[M+H]+.

Example 197

1-[1-(2-Dimethylaminoethyl)piperidine-4-yl]-3-[6-(4-{3-[2-(4-forfinal)acetyl]touraid}phenoxy)pyrimidine-4-yl]-1-metalmachine

After addition of (1S)-(+)-10-camphorsulfonic acid (127 mg) to a solution of crude 3-[6-(4-aminophenoxy)pyrimidine-4-yl]-1-[1-(2-dimethylaminoethyl)piperidine-4-yl]-1-metalmachine (119 mg) in ethanol (3.0 ml) the mixture is stirred for 15 minutes at room temperature. Then, after adding 2-(4-forfinal)acetylsalicylate (4,08 ml, 0,25M solution in toluene), the mixture is stirred at room temperature for 2 hours. The reaction mixture was partitioned between saturated aqueous sodium hydrogen carbonate (10 ml) and ethyl acetate (30 ml). The organic layer was washed with saturated saline and dried over anhydrous sodium sulfate. The dried organic layer is concentrated and the residue purified column chromatography on silica gel (Fuji Silysia NH, eluent: ethyl acetate, then ethyl acetate:methanol = 20:1 to 10:1). The fractions containing the target compound, concentrated and the residue purified by LC-MS (system of water-acetonitrile-triperoxonane acid). The fractions containing the target compound is concentrated and to the residue is added saturated aqueous solution of sodium bicarbonate and the mixture extracted with ethyl acetate. The organic layer is dried over anhydrous sodium sulfate. H is decayed organic layer concentrated. The obtained solid is suspended in diethyl ether. The precipitate is filtered and dried, obtaining specified in the header connection (12,4 mg) as white powder.

Range1H-NMR (CDCl3) δ (ppm): to 1.86 (2H, m), of 2.20 (2H, m), 2,46 (6H, Sirs), 2,62 (4H, m), of 2.92 (3H, c), of 3.07 (2H, m), 3,71 (2H, c), 4,22 (1H, m), 7,12 (2H, m), 7,17 (2H, d, J=8,8 Hz), 7,26-7,31 (5H, m), to 7.59 (1H, c), 7,71 (2H, d, J=8,8 Hz), scored 8.38 (1H, c), 8,46 (1H, Sirs), 12,27 (1H, c).

ESI-MS (m/z): 609[M+H]+.

Example of getting 197-1

1-[1-(2-Dimethylaminoethyl)piperidine-4-yl]-1-methyl-3-[6-(4-nitrophenoxy)pyrimidine-4-yl]urea

After adding triethylamine (0,112 ml) and phenylcarbamate (0,089 ml) to a solution of 6-(4-nitrophenoxy)pyrimidine-4-ylamine (75,0 mg) in tetrahydrofuran (4.0 ml) at room temperature, the mixture is stirred for 30 minutes at the same temperature. The reaction mixture is concentrated and to the residue is added N,N-dimethylformamide (3.0 ml) and N-[1-(2-dimethylaminoethyl)piperidine-4-yl]-N-methylamine (341 mg), after which the mixture was stirred at room temperature for 46 hours. To the reaction mixture are added ethyl acetate (30 ml) and 1 N. aqueous sodium hydroxide solution (20 ml), then stirred at room temperature for 1 hour. Then the reaction mixture evenly. The aqueous layer was extracted with ethyl acetate (50 ml). The organic layer is dried over anhydrous sodium sulfate and concentrated. The obtained solid substance is spenderat in a mixture of diethyl ether:hexane = 1:3. The supernatant is removed and the remainder is dried, obtaining mentioned in the title compound (131 mg, 91,4%) as yellow powder.

Range1H-NMR (CDCl3) δ (ppm): of 1.66 (2H, m), of 1.80 (2H, m), 2,12 (2H, m), and 2.26 (6H, c), 2,47 (4H, m), 2,90 (3H, c), totaling 3.04 (2H, m), 4,17 (1H, m), 7,31 (2H, d, J=9.0 Hz), 7,42 (1H, Sirs), of 7.70 (1H, c), 8,30 (2H, d, J=9,0 Hz), 8,39 (1H, c).

ESI-MS (m/z): 444[M+H]+.

Example of getting 197-2

3-[6-(4-Aminophenoxy)pyrimidine-4-yl]-1-[1-(2-dimethylaminoethyl)piperidine-4-yl]-1-metalmachine

After adding 20% palladium hydroxide on coal (51,8 mg) to a solution of 1-[1-(2-dimethylaminoethyl)piperidine-4-yl]-1-methyl-3-[6-(4-nitrophenoxy)pyrimidine-4-yl]urea (131 mg) in tetrahydrofuran (10.0 ml) and the mixture is stirred for 10.5 hours at room temperature in a hydrogen atmosphere. The catalyst is filtered off and washed with methanol. The filtrate is concentrated and receiving untreated specified in the title compound (122 mg) as a yellow oil.

ESI-MS(m/z): 414[M+H]+.

Example 198

4-[2-(Pyrrolidin-1-yl)ethyl]piperazine-1-carboxylic acid {6-[2-fluoro-4-(3-phenylacetylamino)phenoxy]pyrimidine-4-yl}amide

After dissolving 4-[2-(pyrrolidin-1-yl)ethyl]piperazine-1-carboxylic acid [6-(4-amino-2-pertenece)pyrimidine-4-yl]amide (49 mg) in ethanol (2 ml) under nitrogen atmosphere add D-10-camphorsulfonic acid (53 mg) and the mixture stirred for 5 minutes. To the reaction mixture to 0,2M solution of 2-phenylacetonitrile in toluene (0,684 ml) and stirred for 1 hour. The reaction mixture is distributed between ethyl acetate (50 ml) and saturated aqueous sodium hydrogen carbonate (30 ml). The organic layer was washed with saturated aqueous sodium hydrogen carbonate (30 ml), water (30 ml) and saturated saline (30 ml) in that order, then dried over anhydrous sodium sulfate. The solvent is distilled off under reduced pressure and the resulting residue is purified column chromatography on silica gel (Fuji Silysia NH, eluent: heptane:ethyl acetate = 1:8). The fractions containing the target compound are concentrated under reduced pressure, and then to the obtained residue is added diethyl ether (1.0 ml) and hexane (1.5 ml) to obtain the suspension of solids. The solid is filtered off, dried in the air flow and get listed in the title compound (5.8 mg, 8.4 per cent) in the form of white powder.

Range1H-NMR (CDCl3) δ (ppm): is 1.81 (4H, m), 2.40 a-2,65 (10H, m)to 2.66 (2H, m), 3,55 (4H, m), 3,74 (2H, c), 7,00 was 7.45 (8H, m), of 7.64 (1H, Sirs), 7,86 (1H, DD, J=2.0 a, and 11.6 Hz), with 8.33 (1H, Sirs), 8,44 (1H, m), 12,42 (1H, Sirs).

ESI-MS (m/z): 607[M+H]+.

Example of getting 198-1

4-[2-(Pyrrolidin-1-yl)ethyl]piperazine-1-carboxylic acid [6-(2-fluoro-4-nitrophenoxy)pyrimidine-4-yl]amide

After dissolving 6-(2-fluoro-4-nitrophenoxy)pyrimidine-4-ylamine (100 mg) in tetrahydrofuran (3 ml) in an atmosphere of nitrogen was added triethylamine (0,167 ml) and phenylcarbamate (0,151 ml) PR is stirring in the bath, containing water with ice. The reaction mixture was left to warm to room temperature and stirred for 30 minutes. Then the reaction mixture is distributed between ethyl acetate (50 ml) and saturated aqueous sodium hydrogen carbonate (30 ml). The organic layer is separated and washed with saturated aqueous sodium hydrogen carbonate (30 ml), water (30 ml) and saturated saline (30 ml) in that order, after which it is dried over anhydrous sodium sulfate. The solution is distilled off under reduced pressure, the obtained residue is added N,N-dimethylformamide (3 ml), then add 1-[2-(pyrrolidin-1-yl)ethyl]piperazine (295 mg) in N,N-dimethylformamide (0.5 ml×3) and the mixture is stirred for 18 hours. The reaction mixture is distributed between ethyl acetate (50 ml) and saturated aqueous ammonium chloride (30 ml). The organic layer is separated and washed with saturated aqueous ammonium chloride (30 ml), water (30 ml) and saturated saline (30 ml) in that order, then dried over anhydrous sodium sulfate. The solution is distilled off under reduced pressure and then the resulting residue is purified column chromatography on silica gel (Fuji Silysia NH, eluent: heptane:ethyl acetate = 1:1, ethyl acetate, then ethyl acetate:ethanol = 19:1). The fractions containing the target compound are concentrated under reduced pressure, obtaining the neo is isonoe specified in the title compound (130 mg, 70,7%) in the form of oil pale brown color.

Range1H-NMR (CDCl3) δ (ppm): 1,80 (4H, m), 2.40 a-2,80 (12H, m), of 3.56 (4H, m), 7,34-to 7.50 (2H, m), 7,73 (1H, c), 8,11 (2H, m), 8,32 (1H, m).

Example of getting 198-2

4-[2-(Pyrrolidin-1-yl)ethyl]piperazine-1-carboxylic acid [6-(4-amino-2-pertenece)pyrimidine-4-yl]amide

After adding tetrahydrofuran (3 ml) and methanol (3 ml) to the crude 4-[2-(pyrrolidin-1-yl)ethyl]piperazine-1-carboxylic acid [6-(2-fluoro-4-nitrophenoxy)pyrimidine-4-yl]amide (129 mg) in a nitrogen atmosphere, add 10% palladium on coal (60 mg), and then the atmosphere in the reaction vessel is replaced with hydrogen and the mixture is stirred for 4.5 hours. Then the atmosphere in the reaction vessel is replaced by nitrogen, the catalyst is filtered off and washed with methanol. The filtrate is concentrated under reduced pressure. The resulting residue is purified column chromatography on silica gel (Fuji Silysia NH, eluent: ethyl acetate:methanol = 19:1) and then the fractions containing the target compound are concentrated under reduced pressure, obtaining the crude specified in the header connection (98,4 mg) as an amorphous substance pale yellow color.

Range1H-NMR (CDCl3) δ (ppm): to 1.79 (4H, m), 2,45-2,60 (10H, m), 2,60-2,69 (2H, m), of 3.54 (4H, m), of 3.73 (2H, Sirs), 6,44 (1H, m), 6,50 (1H, DD, J=2,8, 12.0 Hz), 6,98 (1H, m), 7,32 (1H, m), 7,55 (1H, m), at 8.36 (1H, m).

Example 199

1-[6-(2-Fluoro-4-{3-[2-(4-forfinal)acetyl]touraid}phenoxy)pyrimidine-4-the l]-3-(1-methylpiperidin-4-yl)urea

Specified in the title compound (50.2 mg, 44.1 per cent) receive in the form of a powder pale yellow color of the crude 1-[6-(4-amino-2-pertenece)pyrimidine-4-yl]-3-(1-methylpiperidin-4-yl)urea (73,9 mg) and 0,2M solution of 2-(4-forfinal)acetylsalicylate in toluene (1.6 ml).

Range1H-NMR (CDCl3) δ (ppm): 1,41 (2H, m), of 1.80 (2H, m), 2,03 (2H, m), of 2.15 (3H, m), 2,52-of 2.72 (2H, m), 3,49 (1H, m), 3,83 (2H, c), 7,18 (3H, m), 7,26 (2H, m), 7,30 is 7.50 (4H, m), 7,88 (1H, m), of 8.37 (1H, c), 9,48 (1H, Sirs), 11,78 (1H, m).

ESI-MS (m/z): 556[M+H]+.

Example of getting 199-1

1-[6-(4-Amino-2-pertenece)pyrimidine-4-yl]-3-(1-methylpiperidin-4-yl)urea

Untreated specified in the header connection (73,9 mg) are obtained in the form of a yellow oil from 1-[6-(2-fluoro-4-nitrophenoxy)pyrimidine-4-yl]-3-(1-methylpiperidin-4-yl)urea (80 mg).

ESI-MS (m/z): 361[M+H]+.

Example 200

4-(Pyrrolidin-1-yl)piperidine-1-carboxylic acid [4-(4-{3-[2-(4-forfinal)acetyl]touraid}phenoxy)pyridine-2-yl]amide

Specified in the title compound (15.3 mg, 15.5 per cent) receive in the form of a white powder of crude 4-(pyrrolidin-1-yl)piperidine-1-carboxylic acid [4-(4-aminophenoxy)pyridine-2-yl]amide (65,3 mg), D-10-camphorsulfonic acid (79,4 mg) and 0,2M solution of 2-(4-forfinal)acetylsalicylate in toluene (0.2 ml).

Range1H-NMR (CDCl3) δ (ppm): 1.18 to about 1.36 (4H, m), of 1.65 (4H, m), of 1.78 (2H, m), 2,12 (1H, m), 2,38-2,60 (2H, m), of 2.86 (2H, m), 3,82 (2H, c), of 3.96 (2H, m), 6,56 (1H, DD, J=2,0, 5.6 Hz), 7,10-7,29 (4H, m), 7,0-7,56 (3H, m), 7,71 (2H, d, J=8,8 Hz)to 8.12 (1H, d, J=5.6 Hz), 9,19 (1H, Sirs), 11,72 (1H, m), 12,37 (1H, m).

ESI-MS (m/z): 577[M+H]+.

Example of getting 200-1

4-(Pyrrolidin-1-yl)piperidine-1-carboxylic acid [4-(4-aminophenoxy)pyridine-2-yl]amide

Untreated specified in the header connection (65,3 mg) are obtained in the form of a yellow oil of 4-(pyrrolidin-1-yl)piperidine-1-carboxylic acid [4-(4-nitrophenoxy)pyridine-2-yl]amide (87,6 mg), synthesized from [4-(4-nitrophenoxy)pyridine-2-yl]carbamino acid phenyl ester (75 mg), N,N-dimethylformamide (3 ml) and 4-(pyrrolidin-1-yl)piperidine (98,6 mg).

ESI-MS (m/z): 382[M+H]+.

Example 201

3-[6-(2-Fluoro-4-{3-[2-(4-forfinal)acetyl]touraid}phenoxy)pyrimidine-4-yl]-1-methyl-1-[(3S)-1-methylpyrrolidine-3-yl]urea

Specified in the header connection (23,0 mg, 17%) are obtained as white crystals from 3-[6-(4-amino-2-pertenece)pyrimidine-4-yl]-1-methyl-1-[(3S)-1-methylpyrrolidine-3-yl]urea (90 mg), (+)-10-camphorsulfonic acid (53.3 per mg) and a solution of 2-(4-forfinal)acetylsalicylate in toluene (0,1M, 3 ml).

Range1H-NMR (CDCl3) δ (ppm): 1,99 (1H, m)to 2.13 (1H, m), 2,30-to 2.40 (2H, m)2,44 (3H, c), 3,05 (1H, m), is 3.08 (3H, c), 3,24 (1H, m), 3,71 (2H, c), of 4.12 (1H, m), 7,10-7,40 (7H, m), 7,71 (1H, d, J=0.8 Hz), to 7.84 (1H, DD, J=2,4, 11.2 Hz), a 8.34 (1H, d, J=0.8 Hz), 8,42 (1H, Sirs), 12,36 (1H, Sirs).

Example of getting 201-1

3-[6-(2-Fluoro-4-nitrophenoxy)pyrimidine-4-yl]-1-methyl-1-[(3S)-1-methylpyrrolidine-3-yl]urea

Specified in zag is lowke compound (93 mg, 60%) are obtained in the form of white crystals of 4-amino-6-(2-fluoro-4-nitrophenoxy)pyrimidine (100 mg), triethylamine (0,140 ml), phenylcarbamate (0,125 ml), a solution of dihydrochloride of (3S)-1-methyl-3-methylaminopropane (468 mg) in N,N-dimethylformamide (2.5 ml) and triethylamine (0.7 ml).

Range1H-NMR (CDCl3) δ (ppm): 2,00 (1H, m), and 2.14 (1H, m), 2,35 at 2.45 (2H, m), 2,46 (3H, c), of 3.07 (1H, m)to 3.09 (3H, c), with 3.27 (1H, m), 4,10 (1H, m), 7,39 (1H, m), 7,81 (1H, d, J=0.8 Hz), 8.07-a to 8.14 (2H, m), with 8.33 (1H, d, J=0.8 Hz).

Example of getting 201-2

3-[6-(4-Amino-2-pertenece)pyrimidine-4-yl]-1-methyl-1-[(3S)-1-methylpyrrolidine-3-yl]urea

Specified in the title compound (90 mg, quantitative yield) are obtained in the form of a white powder of 3-[6-(2-fluoro-4-nitrophenoxy)pyrimidine-4-yl]-1-methyl-1-[(3S)-1-methylpyrrolidine-3-yl]urea (93 mg).

ESI-MS (m/z): 361[M+H]+.

Example 202

(1S,4S)-5-Methyl-2,5-diazabicyclo[2.2.1]heptane-2-carboxylic acid [6-(2-fluoro-4-{3-[2-(4-forfinal)acetyl]touraid}phenoxy)pyrimidine-4-yl]amide

Specified in the header of the connection (or 48.2 mg, 73%) are obtained in the form of a white powder of (1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]heptane-2-carboxylic acid [6-(4-amino-2-pertenece)pyrimidine-4-yl]amide (42.7 mg), (+)-10-camphorsulfonic acid (27,6 mg) and a solution of 2-(4-forfinal)acetylsalicylate in toluene (0,1M, 1.5 ml).

Range1H-NMR (CDCl3) δ (ppm): or 1.77 (1H, m)of 1.97 (1H, m)2,44 (3H, c), by 2.73 (1H, m), with 2.93 (1H, m)to 3.33 (1H, DD, J=2,4, 8,8 Hz), 3,53 (1H, Sirs), 362 (1H, m), 3,71 (2H, c), of 4.54 (1H, m), 7,00-7,40 (7H, m), of 7.69 (1H, d, J=0.8 Hz), 7,86 (1H, DD, J=2,4, 11.2 Hz), with 8.33 (1H, d, J=0.8 Hz), 8,43 (1H, Sirs), 12,38 (1H, Sirs).

Example of getting 202-1

(1S,4S)-5-Methyl-2,5-diazabicyclo[2.2.1]heptane-2-carboxylic acid [6-(2-fluoro-4-nitrophenoxy)pyrimidine-4-yl]amide

Specified in the title compound (95 mg, 61%) are obtained in the form of a powder pale yellow color of 4-amino-6-(2-fluoro-4-nitrophenoxy)pyrimidine (100 mg), triethylamine (0,139 ml), phenylcarbamate (0,125 ml) and a solution of (1S,4S)-2-methyl-2,5-diazabicyclo[2.2.1]heptane (359 mg) in N,N-dimethylformamide (3.2 ml).

Range1H-NMR (CDCl3) δ (ppm): 1,78 (1H, m)to 1.98 (1H, m), of 2.45 (3H, c), was 2.76 (1H, m), of 2.92 (1H, m)to 3.35 (1H, DD, J=2,4, 8,8 Hz), 3,54 (1H, c), 3,63 (1H, m), 4,56 (1H, W), 7,14 (1H, Sirs), 7,41 (1H, m), 7,79 (1H, c), 8,08-of 8.15 (2H, m), 8,32 (1H, c).

Example of getting 202-2

(1S,4S)-5-Methyl-2,5-diazabicyclo[2.2.1]heptane-2-carboxylic acid [6-(4-amino-2-pertenece)pyrimidine-4-yl]amide

Specified in the title compound (42.7 mg, 49%) are obtained in the form of a white powder of (1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]heptane-2-carboxylic acid [6-(2-fluoro-4-nitrophenoxy)pyrimidine-4-yl]amide (95 mg).

ESI-MS (m/z): 359[M+H]+.

Example 203

3-[6-(2-Fluoro-4-{3-[2-(2-forfinal)acetyl]touraid}phenoxy)pyrimidine-4-yl]-1-methyl-1-(1-methylpiperidin-4-yl)urea

Specified in the title compound (15.3 mg, 17.7 percent) receive in the form of a white powder of 3-[6-(4-amino-2-pertenece)pyrimidine-4-yl]-1-methyl-1-(1-methylpiperidin-yl)urea (57,0 mg), D-10-camphorsulfonic acid (35,3 mg) of the crude 2-(2-forfinal)acetylsalicylate.

Range1H-NMR (CDCl3) δ (ppm): 1,50 to 1.76 (2H, m), is 1.81 (2H, m), 2,12 (2H, m), 2,31 (3H, c), of 2.86-3.04 from (5H, m), of 3.77 (2H, c), 4,20 (1H, m), 7,08 is 7.50 (7H, m), 7,68 (1H, c), 7,87 (1H, DD, J=2,4, and 11.6 Hz), a 8.34 (1H, c), 8,63 (1H, Sirs), 12,36 (1H, Sirs).

ESI-MS (m/z): 592[M+Na]+.

Example 204

3-[6-(2-Fluoro-4-{3-[2-(3-forfinal)acetyl]touraid}phenoxy)pyrimidine-4-yl]-1-methyl-1-(1-methylpiperidin-4-yl)urea

Specified in the title compound (15.3 mg, 17.4 per cent) receive in the form of a white powder of 3-[6-(4-amino-2-pertenece)pyrimidine-4-yl]-1-methyl-1-(1-methylpiperidin-4-yl)urea (of 57.5 mg), D-10-camphorsulfonic acid (35,8 mg) and crude 2-(3-forfinal)acetylsalicylate.

Range1H-NMR (CDCl3) δ (ppm): 1,62-of 1.75 (2H, m), equal to 1.82 (2H, m), 2,12 (2H, m), 2,31 (3H, c), 2,85-to 3.02 (5H, m), of 3.77 (2H, c), 4,20 (1H, m), 7,10-to 7.50 (7H, m), 7,68 (1H, d, J=1.2 Hz), 7,87 (1H, DD, J=2,8, and 11.6 Hz), a 8.34 (1H, d, J=1.2 Hz), 8,59 (1H, Sirs), 12,35 (1H, Sirs).

ESI-MS (m/z): 592[M+Na]+.

Example 205

4-Methylpiperazin-1-carboxylic acid [6-(2-fluoro-4-{3-[2-(4-forfinal)acetyl]touraid}phenoxy)pyrimidine-4-yl]amide

Specified in the title compound (65 mg, 35%) are obtained as white powder from 4-methylpiperazin-1-carboxylic acid [6-(4-amino-2-pertenece)pyrimidine-4-yl]amide (119 mg), (+)-10-camphorsulfonic acid (79,9 mg) and a solution of 2-(4-forfinal)acetylsalicylate in toluene (0,1M, and 4.5 ml).

Range1NMR (CDCl 3) δ (ppm): was 2.34 (3H, c), 2,42-of 2.50 (4H, m), 3,52-to 3.58 (4H, m), 3,71 (2H, c), 7,10-7,40 (7H, m), 7,63 (1H, d, J=0.8 Hz), 7,86 (1H, DD, J=2,4, 11.2 Hz), with 8.33 (1H, d, J=0.8 Hz), to 8.45 (1H, Sirs), 12,38 (1H, Sirs).

Example of getting 205-1

4-Methylpiperazin-1-carboxylic acid [6-(2-fluoro-4-nitrophenoxy)pyrimidine-4-yl]amide

Specified in the header connection (135,5 mg, 72%) are obtained as white powder from 4-amino-6-(2-fluoro-4-nitrophenoxy)pyrimidine (125 mg), triethylamine (0,180 ml), phenylcarbamate (0,160 ml) and 1-methylpiperazine (0,424 ml).

Range1H-NMR (CDCl3) δ (ppm): 2,35 (3H, c), a 2.45-2.49 USD (4H, m), 3,55-3,59 (4H, m), 7,39-7,44 (2H, m), 7,73 (1H, c), 8,08-of 8.15 (2H, m), 8,32 (1H, c).

Example of getting 205-2

4-Methylpiperazin-1-carboxylic acid [6-(4-amino-2-pertenece)pyrimidine-4-yl]amide

Specified in the title compound (119 mg, 96%) are obtained as white powder from 4-methylpiperazin-1-carboxylic acid [6-(2-fluoro-4-nitrophenoxy)pyrimidine-4-yl]amide (135 mg).

ESI-MS (m/z): 369[M+Na]+.

Example 206

1-(3-Dimethylaminopropyl)-3-[6-(2-fluoro-4-{3-[2-(4-forfinal)acetyl]touraid}phenoxy)pyrimidine-4-yl]-1-metalmachine

Specified in the title compound (35.4 mg, 21%) are obtained in the form of a white powder of 3-[6-(4-amino-2-pertenece)pyrimidine-4-yl]-1-(3-dimethylaminopropyl)-1-metalmachine (111 mg), (+)-10-camphorsulfonic acid (72,5 mg) and a solution of 2-(4-forfinal)acetylsalicylate in toluene (0,1M, 4,0 ml).

Range1H-NMR (CDCl3

Example of getting 206-1

1-(3-Dimethylaminopropyl)-3-[6-(2-fluoro-4-nitrophenoxy)pyrimidine-4-yl]-1-metalmachine

Specified in the title compound (128 mg, 68%) are obtained in the form of white crystals of 4-amino-6-(2-fluoro-4-nitrophenoxy)pyrimidine (120 mg), triethylamine (0,167 ml), phenylcarbamate (0,150 ml) and N,N,N'-trimethyl-1,3-propandiamine (0.45 ml).

Range1H-NMR (CDCl3) δ (ppm): 1,75-of 1.85 (2H, m), 2,31 (6H, c), 2,35-to 2.41 (2H, m)to 2.94 (3H, c), 3,40-3,44 (2H, m), 7,40 (1H, m), 7,60 (1H, d, J=0.8 Hz), 8,06-8,13 (2H, m), 8,31 (1H, d, J=0.8 Hz).

Example of getting 206-2

3-[6-(4-Amino-2-pertenece)pyrimidine-4-yl]-1-(3-dimethylaminopropyl)-1-metalmachine

Specified in the title compound (111 mg) was obtained as colorless oil from 1-(3-dimethylaminopropyl)-3-[6-(2-fluoro-4-nitrophenoxy)pyrimidine-4-yl]-1-metalmachine (128 mg).

ESI-MS (m/z): 363[M+H]+.

Example 207

3-(Pyrrolidin-1-yl)azetidin-1-carboxylic acid [6-(2-fluoro-4-{3-[2-(4-pertenece)acetyl]touraid}phenoxy)pyrimidine-4-yl]amide

Specified in the title compound (8.3 mg/, 6,53%) are obtained in the form of a white powder from 3-(pyrrolidin-1-yl)azetidin-1-carboxylic acid [6-(4-amino-2-pertenece)pyrimidine-4-yl]amide (ESI-MS (m/z): 395[M+Na]+)synthesized from 3-(pyrrolidin-1-yl)azetidin-1-carboxylic acid[6-(2-fluoro-4-nitrophenoxy)pyrimidine-4-yl]amide (90,3 mg), (1S)-(+)-10-camphorsulfonic acid (8.5 mg) and 2-(4-forfinal)acetylsalicylate (0,2M solution in toluene, of 1.12 ml).

Range1H-NMR (CDCl3) δ (ppm): of 1.84 (4H, m), 2,52 (4H, m), 3,39 (1H, m), 3,71 (2H, c)to 4.01 (2H, m), 4,13 (2H, m), 6.89 in (1H, c), 7,12 (2H, m), 7,21 (2H, m), 7,29 (1H, m), of 7.36 (1H, m), the 7.65 (1H, d, J=0.8 Hz), 7,86 (1H, DD, J=2,4, and 11.6 Hz), with 8.33 (1H, d, J=0.8 Hz), of 8.47 (1H, c), 12,38 (1H, c).

ESI-MS (m/z): (neg.): 566[M-H]-.

Example of getting 207-1

3-(Pyrrolidin-1-yl)azetidin-1-carboxylic acid [6-(2-fluoro-4-nitrophenoxy)pyrimidine-4-yl]amide

Specified in the header connection (to 90.3 mg, 37.4 per cent) obtained as an amorphous substance pale-yellow 6-(2-fluoro-4-nitrophenoxy)pyrimidine-4-ylamine (150 mg), triethylamine (0,209 ml), phenylcarbamate (0,150 ml), DATEFORMAT 3-(pyrrolidin-1-yl)azetidine (1.06 g) and triethylamine (1.0 ml).

Range1H-NMR (CDCl3) δ (ppm): 1,68 (4H, m), 2,53 (4H, m), 3,39 (1H, m), a 4.03 (2H, m)to 4.16 (2H, m), 7,06 (1H, c), 7,41 (1H, m), 7,55 (1H, d, J=0.8 Hz), 8,08-to 8.14 (2H, m), 8,32 (1H, d, J=0.8 Hz).

ESI-MS (m/z): 425[M+Na]+.

Example 208

3-Dimethylimidazolidin-1-carboxylic acid [6-(2-fluoro-4-{3-[2-(4-forfinal)acetyl]touraid}phenoxy)pyrimidine-4-yl]amide

Specified in the title compound (22 mg) are obtained in the form of a white powder of 1/2 of the amount of crude 3-dimethylimidazolidin-1-carboxylic acid [6-(4-amino-2-pertenece)pyrimidine-4-yl]amide (ESI-MS (m/z): 369[M+Na]+)synthesized from 3-dimethylimidazolidin-1-carbon is acid [6-(2-fluoro-4-nitrophenoxy)pyrimidine-4-yl]amide (88 mg), (1S)-(+)-10-camphorsulfonic acid (from 25.8 mg) and 2-(4-forfinal)acetylsalicylate (0,2M solution in toluene, 0,556 ml).

Range1H-NMR (CDCl3) δ (ppm): 2,20 (6H, c), and 3.16 (1H, m), 3,71 (2H, c), of 3.95 (2H, m), 4.09 to (2H, m), 6,97 (1H, c), to 7.09 (2H, m), 7,21 (2H, m), 7,26-7,37 (2H, m), 7,66 (1H, c), 7,86 (1H, DD, J=2,4, 11.2 Hz), with 8.33 (1H, c), a total of 8.74 (1H, Sirs), 12,41 (1H, c).

ESI-MS (m/z): 564[M+Na]+.

Example of getting 208-1

3-Dimethylimidazolidin-1-carboxylic acid [6-(2-fluoro-4-nitrophenoxy)pyrimidine-4-yl]amide

Specified in the header connection (88,0 mg, 39,0%) was obtained as an amorphous substance pale-yellow 6-(2-fluoro-4-nitrophenoxy)pyrimidine-4-ylamine (150 mg), phenylcarbamate (0,150 ml), the crude DATEFORMAT 3-(pyrrolidin-1-yl)azetidine (1.28 g) and triethylamine.

Range1H-NMR (CDCl3) δ (ppm): of 2.21 (6H, c)3,18 (1H, m), of 3.97 (2H, m), of 4.12 (2H, m), 7,00 (1H, c), 7,41 (1H, m), 7,76 (1H, c), 8,11 (2H, m), 8,32 (1H, c).

ESI-MS (m/z): 398[M+Na]+.

Example 209

4-{[(3R)-3-(Dimethylaminomethyl)pyrrolidin-1-yl]carbylamine}-6-(2-fluoro-4-{3-[2-(4-forfinal)acetyl]touraid}phenoxy)pyrimidine

Specified in the header connection (41,4 mg, 29%) are obtained as white powder from 4-(4-amino-2-pertenece)-6-{[(3R)-3-(dimethylaminomethyl)pyrrolidin-1-yl]carbylamine}pyrimidine (95,3 mg), (+)-10-camphorsulfonic acid (of 57.5 mg) and a solution of 2-(4-forfinal)acetylsalicylate in toluene (0,1M, 3.3 ml).

Range1H-NMR (CDCl3) δ (ppm): 1,72 (1H, m), 2,10 (1, m in), 2.25 (6H, c), 2,29 of-2.32 (2H, m)of 2.50 (1H, m), 3,20 (1H, m), 3,40-3,70 (3H, m), 3,71 (2H, c), 7,10-7,40 (7H, m), of 7.70 (1H, c), 7,86 (1H, DD, J=2,4, 11.2 Hz), 8,32 (1H, c), 8,44 (1H, Sirs), 12,38 (1H, Sirs).

Example of getting 209-1

4-{[(3R)-3-(Dimethylaminomethyl)pyrrolidin-1-yl]carbylamine}-6-(2-fluoro-4-nitrophenoxy)pyrimidine

Specified in the title compound (112 mg, 55%) was obtained as colorless oil from 4-amino-6-(2-fluoro-4-nitrophenoxy)pyrimidine (125 mg), phenylcarbamate (0,150 ml), a solution of dihydrochloride of (3R)-3-(dimethylaminomethyl)pyrrolidine (603 mg) in N,N-dimethylformamide (3.5 ml) and triethylamine.

Range1H-NMR (CDCl3) δ (ppm): 2,05-of 2.25 (2H, m), and 2.26 (6H, c), 2,30 of-2.32 (2H, m), 2,52 (1H, m), up 3.22 (1H, DD, J=3.2, and 9.6 Hz), 3,48 (1H, m), 3,60-3,70 (2H, m), 7.23 percent (1H, Sirs), 7,41 (1H, m), 7,79 (1H, d, J=0.8 Hz), 8.07-a 8,14 (2H, m), 8,31 (1H, d, J=0.8 Hz).

Example of getting 209-2

4-(4-Amino-2-pertenece)-6-{[(3R)-3-(dimethylaminomethyl)pyrrolidin-1-yl]carbylamine}pyrimidine

Specified in the header of the connection (for 95.3 mg, 92%) are obtained in the form of oil is pale-yellow 4-{[(3R)-3-(dimethylaminomethyl)pyrrolidin-1-yl]carbylamine}-6-(2-fluoro-4-nitrophenoxy)pyrimidine (112 mg).

ESI-MS (m/z): 375[M+H]+.

Example 210

3-[6-(2-Fluoro-4-{3-[2-(4-forfinal)acetyl]touraid}phenoxy)pyrimidine-4-yl]-1-methyl-1-[(3S)-(1-methylpyrrolidine-3-yl)methyl]urea

Specified in the header connection (with 76.8 mg, 32%) are obtained in the form of a white powder of 3-[6-(4-amino-2-pertenece)pyrimidine-4-yl]-1-methyl-1-[(3S)-(1-metile Raiden-3-yl)methyl]urea (162 mg), (+)-10-camphorsulfonic acid (to 97.1 mg) and a solution of 2-(4-forfinal)acetylsalicylate in toluene (0,1M, 5.6 ml).

Range1H-NMR (CDCl3) δ (ppm): 1,48 (1H, m), a 2.01 (1H, m), of 2.21 (1H, m), 2,32 (1H, m), of 2.38 (3H, c), 2,48 (1H, m)to 2.66 (1H, m), 2,98 (3H, c), 3,02-3,20 (2H, m), 3,49 (1H, DD, J=11,2, 14,8 Hz), 3,71 (2H, c), 7,10-7,40 (7H, m)to 7.61 (1H, c), a 7.85 (1H, DD, J=2,4, 11.2 Hz), with 8.33 (1H, c), 8,48 (1H, Sirs), 12,37 (1H, Sirs).

Example of getting 210-1

3-[6-(2-Fluoro-4-nitrophenoxy)pyrimidine-4-yl]-1-methyl-1-[(3S)-(1-methylpyrrolidine-3-yl)methyl]urea

Specified in the title compound (174 mg, 86%) was obtained as colorless oil from 4-amino-6-(2-fluoro-4-nitrophenoxy)pyrimidine (125 mg), triethylamine (0,167 ml), phenylcarbamate (0,150 ml) and a solution of (3R)-1-methyl-3-(methylaminomethyl)pyrrolidine (449 mg) in N,N-dimethylformamide (3.5 ml).

ESI-MS (m/z): 427[M+Na]+.

Example of getting 210-2

3-[6-(4-Amino-2-pertenece)pyrimidine-4-yl]-1-methyl-1-[(3S)-(1-methylpyrrolidine-3-yl)methyl]urea

Specified in the title compound (163 mg) are obtained in the form of oil is pale-yellow 3-[6-(2-fluoro-4-nitrophenoxy)pyrimidine-4-yl]-1-methyl-1-[(3S)-(1-methylpyrrolidine-3-yl)methyl]urea (174 mg).

ESI-MS (m/z): 375[M+H]+.

Example 211

4-(Pyrrolidin-1-yl)piperidine-1-carboxylic acid [6-(2-fluoro-4-{3-[2-(4-forfinal)acetyl]ureido}phenoxy)pyrimidine-4-yl]amide

Specified in the title compound, which accounted for 98.9 mg, 30.3 per cent) are obtained as white powder from 4-(pyrrolidin-1-yl)piperidine-1-ka is oil acid [6-(4-amino-2-pertenece)pyrimidine-4-yl]amide (226 mg) and 1,0M solution of 2-(4-forfinal)acetylacetonate in N,N-dimethylformamide (1.7 ml) in nitrogen atmosphere.

Range1H-NMR (CDCl3) δ (ppm): 1.50 is by 1.68 (2H, m), of 1.80 (4H, m)of 1.97 (2H, m), 2,24 (1H, m), 2,58 (4H, m), 3.04 from (2H, m), and 3.72 (2H, c), was 4.02 (2H, m), 7,10 (2H, m), 7,14-7,21 (2H, m), 7.24 to 7,34 (2H, m), 7,38 (1H, Sirs), 7,56-7,66 (2H, m), of 7.96 (1H, Sirs), to 8.34 (1H, Sirs), 10,53 (1H, Sirs).

ESI-MS (m/z): 602[M+Na]+.

Example 212

4-Dimethylaminopyridine-1-carboxylic acid [4-(3-fluoro-4-{3-[2-(4-forfinal)acetyl]touraid}phenoxy)pyridine-2-yl]amide

Specified in the title compound (18.5 mg) are obtained in the form of a white powder of 1/2 of the amount of crude 4-dimethylaminopyridine-1-carboxylic acid [4-(4-amino-3-pertenece)pyridine-2-yl]amide (ESI-MS (m/z): 374[M+H]+), synthesized from benzyl (4-{2-[(4-dimethylaminopyridine-1-carbonyl)amino]pyridine-4-yloxy}-2-forfinal)carbamate (122 mg), (1S)-(+)-camphorsulfonic acid (55,8 mg) and 0,2M solution of 2-(4-forfinal)acetylsalicylate in toluene (1,12 ml).

Range1H-NMR (CDCl3) δ (ppm): 1,42-of 1.53 (2H, m), a 1.88 (2H, m), is 2.30 (6H, c), is 2.40 (1H, m), 2.91 in (2H, m), and 3.72 (2H, c), of 4.12 (2H, m), to 6.57 (1H, DD, J=2.0 a, 6,0 Hz)6,91 (2H, d, J=8,4 Hz), 6,93-7,14 (2H, m), 7,25-7,31 (2H,, m), 7,37 (1H, Sirs), to 7.68 (1H, d, J=2.0 Hz), 8,08 (1H, d, J=6.0 Hz), 8,32 (1H, m), 8,79 (1H, Sirs), 12,31 (1H, c).

ESI-MS (m/z): 569[M+H]+.

Example 213

4-(Pyrrolidin-1-yl)piperidine-1-carboxylic acid [4-(3-fluoro-4-{3-[2-(4-forfinal)acetyl]ureido}phenoxy)pyridine-2-yl]amide

Specified in the title compound (2.6 mg) are obtained in the form of a powder pale yellow color of 1/2 of the amount of 4-(pyrrolidin-1-reparacin-1-carboxylic acid [4-(4-amino-3-pertenece)pyridine-2-yl]amide (ESI-MS (m/z: 400[M+H] +), synthesized from benzyl [2-fluoro-4-(2-{[4-(pyrrolidin-1-yl)piperidine-1-carbonyl]amino}pyridine-4-yloxy)phenyl]carbamate (155 mg) and 1,0M solution of 2-(4-forfinal)acetylacetonate in toluene (0,635 ml).

Range1H-NMR (CDCl3) δ (ppm): 1.55V (2H, m), equal to 1.82 (4H, m), of 1.95 (2H, m), is 2.30 (1H, m)of 2.64 (4H, m), 2,96 (2H, m), of 3.73 (2H, c), Android 4.04 (2H, m), of 6.52 (1H, DD, J=2,0, 5.6 Hz), 6.87 in-6,92 (2H, m), 7,07 for 7.12 (2H, m), 7,26-7,32 (2H, m), a 7.62 (2H, d, J=2.0 Hz), with 8.05 (1H, d, J=5.6 Hz), 8,15 (1H, m), 8,23 (1H, c), 10,66 (1H, c).

ESI-MS (m/z): 579[M+H]+.

Example 214

4-Dimethylaminopyridine-1-carboxylic acid [4-(3-fluoro-4-{3-[2-(4-forfinal)acetyl]ureido}phenoxy)pyridine-2-yl]amide

Specified in the title compound (0.55 mg, 0,83%) receive from 1/2 the number of 4-dimethylaminopyridine-1-carboxylic acid [4-(4-amino-3-pertenece)pyridine-2-yl]amide (ESI-MS (m/z): 374[M+H]+), synthesized from benzyl (4-{2-[(4-dimethylaminopyridine-1-carbonyl)amino]pyridine-4-yloxy}-2-forfinal)carbamate (122 mg) and 1,0M solution of 2-(4-forfinal)acetylacetonate in toluene (0,360 ml).

Range1H-NMR (CDCl3) δ (ppm): 1,42-of 1.55 (2H, m), 1,90 (2H, m), 2,33 (6H, c), 2,43 (1H, m), 2,90 (2H, m), of 3.73 (2H, c), of 4.13 (2H, m), 6,53 (1H, DD, J=2,0, 5.6 Hz), 6,85-6,92 (2H, m), 7,11 (2H, m), 7,29 (2H, m), 7,45-7,69 (3H, m), with 8.05 (1H, d, J=5.6 Hz), 8,16 (1H, m), 10,13 (1H, c).

ESI-MS (m/z): 553[M+H]+, 575[M+Na]+.

Example 215

1-[4-(3-Fluoro-4-{3-[2-(4-forfinal)acetyl]touraid}phenoxy)pyridine-2-yl]-3-(1-methylpiperidin-4-yl)urea

Specified in the header connection (18,5 m is) get in the form of a white powder of 1/2 the number of 1-[4-(4-amino-3-pertenece)pyridine-2-yl]-3-(1-methylpiperidin-4-yl)urea, synthesized from crude benzyl (2-fluoro-4-{2-[3-(1-methylpiperidin-4-yl)ureido]pyridine-4-yloxy}phenyl)carbamate (97,0 mg), (1S)-(+)-10-camphorsulfonic acid (51,6 mg) and 2-(4-forfinal)acetylsalicylate (0,2M solution in toluene, 0,833 ml).

Range1H-NMR (CDCl3) δ (ppm): 1,58 is 1.70 (2H, m), 1,98 e 2.06 (2H, m)to 2.18 (1H, m), is 2.30 (3H, c), a 2.75 (2H, m), 3,76 (3H, c), 3,81 (1H, m), 6,18 (1H, d, J=2.0 Hz), 6,55 (1H, DD, J=2.0 a, 6,0 Hz), 6,90 (2H, m), 7,10 (2H, m,), 7,28-7,33 (2H, m), 8,08 (1H, d, J=6.0 Hz), 8,30 (1H, m), 9,43 (1H, shears), 12,38 (1H, c).

ESI-MS (m/z): 555[M+H]+.

Example of getting 215-1

Benzyl (2-fluoro-4-{2-[3-(1-methylpiperidin-4-yl)ureido]pyridine-4-yloxy}phenyl)carbamate

Untreated specified in the title compound (97 mg) are obtained in the form of oil pale yellow 1/6 of the number of intermediate compounds obtained using benzyl [4-(2-aminopyridine-4-yloxy)-2-forfinal]carbamate (2.1 g), triethylamine (2,49 ml) and phenylcarbamate (1,64 ml) and 4-amino-1-methylpiperidine (566 mg).

ESI-MS (m/z): 494[M+H]+.

Example 216

4-{[(3R)-3-Dimethylaminopropan-1-yl]carbylamine}-6-(2-fluoro-4-{3-[2-(4-forfinal)acetyl]touraid}phenoxy)pyrimidine

Specified in the header connection (88.9 mg, 47%) are obtained as white powder from 4-(4-amino-2-pertenece)-6-{[(3R)-3-dimethylaminopropan-1-yl]carbylamine}pyrimidine (130 mg), (+)-10-camphorsulfonic acid (78.5 per mg) and a solution of 2-(4-forfinal)acetylsalicylate in toluene (0,2M, 2,75 ml).

Range1H-NMR (CDCl3) δ (ppm): 1,92 (1H, m), of 2.21 (1H, m), is 2.30 (6H, c), 2,78 (1H, m), 3,26 (1H, m), 3,40-to 3.52 (1H, m), 3,64-a-3.84 (2H, m), and 3.72 (2H, c), 7,10-7,40 (7H, m), of 7.70 (1H, d, J=0.8 Hz), 7,87 (1H, DD, J=2,4, 11.2 Hz), a 8.34 (1H, d, J=0.8 Hz), 8,44 (1H, Sirs), KZT 12.39 (1H, Sirs).

Example of getting 216-1

4-{[(3R)-3-Dimethylaminopropan-1-yl]carbylamine}-6-(2-fluoro-4-nitrophenoxy)pyrimidine

Specified in the title compound (132 mg, 68%) are obtained in the form of a powder pale yellow color of 4-amino-6-(2-fluoro-4-nitrophenoxy)pyrimidine (125 mg), triethylamine (0,167 ml), phenylcarbamate (0,150 ml) and (3R)-3-dimethylaminopyridine (0,330 ml).

Example of getting 216-2

4-(4-Amino-2-pertenece)-6-{[(3R)-3-dimethylaminopropan-1-yl]carbylamine}pyrimidine

Specified in the title compound (130 mg) are obtained as white powder from 4-{[(3R)-3-dimethylaminopropan-1-yl]carbylamine}-6-(2-fluoro-4-nitrophenoxy)pyrimidine (132 mg).

ESI-MS (m/z): 383[M+Na]+.

Example 217

3-[6-(2-Fluoro-4-{3-[2-(4-pertenece)acetyl]touraid}phenoxy)pyrimidine-4-yl]-1-methyl-1-[3-(pyrrolidin-1-yl)propyl]urea

Specified in the header connection (43,8 mg, 23.3 per cent) receive in the form of a white powder of 3-[6-(4-amino-2-pertenece)pyrimidine-4-yl]-1-methyl-1-[3-(pyrrolidin-1-yl)propyl]urea (ESI-MS (m/z): 389[M+H]+)synthesized from 3-[6-(2-fluoro-4-nitrophenoxy)pyrimidine-4-yl]-1-methyl-1-[3-(pyrrolidin-1-yl)propyl]urea (135 mg), (1S)-(+)-10-camphorsulfonic the th acid (142 mg) and 2-(4-forfinal)acetylsalicylate (0,2M solution in toluene, 3.42 ml).

Range1H-NMR (CDCl3) δ (ppm): 1,78 (2H, m), a 1.96 (4H, m)of 2.50 (2H, m), 2.57 m (4H, m), with 2.93 (3H, c), of 3.43 (2H, m), 3,71 (2H, c), 7,12 (2H, m), 7,21 (1H, m), 7,25-to 7.35 (3H, m), 7,51 (1H, c), to 7.84 (1H, DD, J=2,4, and 11.6 Hz), of 8.28 (1H, c), 8,51 (1H, c), 11,54 (1H, Sirs), 12,36 (1H, c).

ESI-MS (m/z): 584[M+H]+.

Example of getting 217-1

3-[6-(2-Fluoro-4-nitrophenoxy)pyrimidine-4-yl]-1-methyl-1-[3-(pyrrolidin-1-yl)propyl]urea

Specified in the title compound (135 mg, 67.2 per cent) receive in the form of crystals of a pale-yellow 6-(2-fluoro-4-nitrophenoxy)pyrimidine-4-ylamine (120 mg), triethylamine (0,334 ml), phenylcarbamate (0,181 ml) and methyl-(3-pyrrolidin-1-ylpropyl)amine (341 mg).

Range1H-NMR (CDCl3) δ (ppm): 1,80 (2H, m), a 1.96 (4H, m), 2,52 (2H, t, J=6.0 Hz), 2,58 (4H, m)to 2.94 (3H, c), of 3.45 (2H, t, J=6.0 Hz), 7,40 (1H, m), 7,60 (1H, c), 8.07-a 8,13 (2H, m), compared to 8.26 (1H, c), 11,64 (1H, Sirs).

ESI-MS (m/z): 419[M+H]+.

Example 218

3-[6-(2-Fluoro-4-{3-[2-(4-pertenece)acetyl]touraid}phenoxy)pyrimidine-4-yl]-1-methyl-1-[3-(azetidin-1-yl)propyl]urea

Specified in the title compound (12.9 mg, 8,81%) are obtained in the form of a white powder of 3-[6-(4-amino-2-pertenece)pyrimidine-4-yl]-1-methyl-1-[3-(azetidin-1-yl)propyl]urea (ESI-MS (m/z): 375[M+H]+, 397[M+Na]+)synthesized from 3-[6-(2-fluoro-4-nitrophenoxy)pyrimidine-4-yl]-1-methyl-1-[3-(azetidin-1-yl)propyl]urea (104 mg), (1S)-(+)-10-camphorsulfonic acid (142 mg) and 0,2M solution (4-forfinal)acetylsalicylate in toluene (2,73 ml).

Range1 H-NMR (CDCl3) δ (ppm): 1,63 (2H, m), and 2.26 (2H, m), 2,46 (2H, m), 2,89 (3H, c), 3,29 (4H, m), 3,37 (2H, m), 3,71 (2H, c), 7,12 (2H, m), 7,29-to 7.35 (4H, m), 7,52 (1H, c), a 7.85 (1H, DD, J=2,4, and 11.6 Hz), 8,35 (1H, c), 8,48 (1H, c), 12,36 (1H, c).

ESI-MS (m/z): 570[M+H]+.

Example of getting 218-1

tert-Butyl (3-azetidin-1-yl-3-oxopropyl)carbamate

After adding the hydrochloride of azetidine (2,96 g) to a solution of triethylamine (4,42 ml) in N,N-dimethylformamide, the mixture is stirred for 10 minutes at room temperature. Add Boc-beta-ALA-OH (5,00 g), the hydrochloride of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (to 7.59 g) and 1-hydroxybenzotriazole (5.35 g), after which the mixture was stirred at room temperature for 3 days. The reaction mixture is distributed between ethyl acetate and saturated salt solution. The organic layer was washed with saturated saline and dried over anhydrous sodium sulfate. Then the dried organic layer is concentrated under reduced pressure. The residue is purified column chromatography on silica gel (eluent: ethyl acetate, then ethyl acetate:methanol = 10:1). The fractions containing the target compound are concentrated under reduced pressure, obtaining specified in the header of the connection (of 5.99 g, 99.4 per cent) in the form of oil pale yellow color.

Range1H-NMR (CDCl3) δ (ppm): USD 1.43 (9H, c), 2,28 (4H, m), 3,37 (2H, m), a 4.03 (2H, m), of 4.12 (2H, m), 5,27 (1H, Sirs).

ESI-MS (m/z): 251[M+Na]+.

Example of getting 218-2

METI is-(3-azetidin-1-ylpropyl)Amin

The aluminum lithium hydride (2,98 g) is gradually added to a solution of tert-butyl (3-azetidin-1-yl-3-oxopropyl)carbamate (of 5.99 g) in tetrahydrofuran (150 ml) under stirring and cooling in a bath with ice. The mixture is stirred under nitrogen atmosphere for 15 minutes in a bath with ice and within 45 minutes at room temperature. Then, it is heated and stirred for 8 hours at 80°C in nitrogen atmosphere. Next, the reaction mixture is heated under reflux for 34 hours at 100°C in nitrogen atmosphere. Then it is cooled in a bath with ice. While stirring, water (2,98 ml), 5 N. aqueous sodium hydroxide solution (2,98 ml) and water (8,94 ml) in that order, after which the mixture was stirred at room temperature for 3 days. Then the insoluble matter is filtered off. The filtrate is concentrated under reduced pressure, obtaining specified in the header connection (2,78 g, 82,8%) as a brown oil.

Range1H-NMR (CDCl3) δ (ppm): of 1.52 (2H, m), is 2.05 (2H, m), is 2.41 (3H, c), 2,43 (2H, m), 2,59 (2H, m), 3,15 (4H, m).

ESI-MS (m/z): 129[M+H]+.

Example of getting 218-3

3-[6-(2-Fluoro-4-nitrophenoxy)pyrimidine-4-yl]-1-methyl-1-[3-(azetidin-1-yl)propyl]urea

Specified in the title compound (104 mg, 53,6%) is obtained from 6-(2-fluoro-4-nitrophenoxy)pyrimidine-4-ylamine (120 mg), triethylamine (0,334 ml), phenylcarbamate (0,181 ml) and methyl-(3-azetidin-ylpropyl)amine (341 mg).

Range1H-NMR (CDCl3) δ (ppm): of 1.65 (2H, m), and 2.27 (2H, m), 2,47 (2H, t, J=6.0 Hz), 2.91 in (3H, c), 3,30 (4H, m)to 3.38 (2H, t, J=5.6 Hz), 7,41 (1H, DD, J=7,0, 9.0 Hz), to 7.61 (1H, c), 8.07-a 8,13 (2H, m), a 8.34 (1H, c), 12,56 (1H, Sirs).

ESI-MS (m/z): 405[M+H]+.

Example 219

(3S)-3-Dimethylaminomethylene-1-carboxylic acid [4-(3-fluoro-4-{3-[2-(4-forfinal)acetyl]touraid}phenoxy)pyridine-2-yl]amide

Specified in the title compound (17.5 mg) are obtained in the form of a white powder of (3S)-3-dimethylaminomethylene-1-carboxylic acid [4-(4-amino-3-pertenece)pyridine-2-yl]amide synthesized from crude benzyl (4-{2-[(3S)-3-dimethylaminomethylene-1-carbonyl]amino}pyridine-4-yloxy)-2-forfinal)carbamate (128 mg), (1S)-(+)-10-camphorsulfonate acid (58.5 mg) and 2-(4-forfinal)acetylsalicylate (1.89 ml, 0,2M solution in toluene).

Range1H-NMR (CDCl3) δ (ppm): 1,70 (1H, m), of 2.08 (1H, m), 2,24 (6H, c), of 2.28 (2H, m), 2,47 (1H, m), 3,17 (1H, m), of 3.43 (1H, m), 3,54-3,68 (2H, m), and 3.72 (2H, c), 6,55 (1H, DD, J=2.0 a, 6,0 Hz), 6,92 (2H, d, J=8,8 Hz), 7,11 (3H, m), 7,26-7,31 (2H, m), 7,76 (1H, d, J=2.0 Hz), 8,07 (1H, d, J=6.0 Hz), 8,32 (1H, m), 8,67 (1H, c), 12,29 (1H, c).

ESI-MS (m/z): 569[M+H]+.

Example of getting 219-1

Benzyl [(4-{2-[(3S)-3-dimethylaminomethylene-1-carbonyl]amino}pyridine-4-yloxy)-2-forfinal]carbamate

Untreated specified in the title compound (128 mg) obtained from benzyl [4-(2-aminopyridine-4-yloxy)-2-forfinal]carbamate (300 mg), phenylcarbamate (0,266 ml), dihydrochloride 3S)-3-(dimethylaminomethyl)pyrrolidine (4,25 ml, 1,0M solution in N,N-dimethylformamide and triethylamine.

Example 220

3-[6-(2-Fluoro-4-{3-[2-(4-forfinal)acetyl]touraid}phenoxy)pyrimidine-4-yl]-1-methyl-1-[4-(pyrrolidin-1-yl)butyl]urea

Specified in the header of the connection region (13.4 mg, 12.7 per cent) receive in the form of a powder pale yellow 3-[6-(4-amino-2-fluoro-phenoxy)pyrimidine-4-yl]-1-methyl-1-[4-(pyrrolidin-1-yl)butyl]urea (ESI-MS (m/z): 403[M+H]+)synthesized from 3-[6-(2-fluoro-4-nitrophenoxy)pyrimidine-4-yl]-1-methyl-1-[4-(pyrrolidin-1-yl)butyl]urea (76 mg), (1S)-(+)-10-camphorsulfonic acid (30,8 mg) and 2-(4-forfinal)acetylsalicylate.

Range1H-NMR (CDCl3) δ (ppm): 1,59 (4H, m), is 1.81 (4H, m), of 2.56 (6H, m), 3.04 from (3H, c), 3,39 (2H, m), 3,71 (2H, c), 7,12 (3H, m), 7,19-7,31 (3H, m), 7,35 (1H, m), EUR 7.57 (1H, Sirs), to 7.68 (1H, d, J=1.2 Hz), the 7.85 (1H, DD, J=to 2.4, 11.2 Hz), with 8.33 (1H, d, J=1.2 Hz), 12,38 (1H, c).

ESI-MS (m/z): 598[M+H]+.

Example of getting 220-1

3-[6-(2-Fluoro-4-nitrophenoxy)pyrimidine-4-yl]-1-methyl-1-[4-(pyrrolidin-1-yl)butyl]urea

Specified in the title compound (76 mg, 54.9 percent) receive in the form of crystals of a pale-yellow 6-(2-fluoro-4-nitrophenoxy)pyrimidine-4-ylamine (80 mg), triethylamine (0,166 ml), phenylcarbamate (0,124 ml) and methyl-[4-(pyrrolidin-1-yl)butyl]amine (250 mg).

Range1H-NMR (CDCl3) δ (ppm): 1,54-1,72 (4H, m), of 1.80 (4H, m), 2,52 (6H, m), 3.04 from (3H, m), 3,40 (2H, m), 7,41 (1H, m), 7,74 (1H, Sirs), 7,78 (1H, c), 8,11 (2H, m), 8,32 (1H, c).

ESI-MS (m/z): 433[M+H]+.

Example 221

1-[1-(3-Dimethyl isopropyl)piperidine-4-yl]-3-[6-(2-fluoro-4-{3-[2-(4-forfinal)acetyl]touraid}phenoxy)pyrimidine-4-yl]-1-metalmachine

Specified in the title compound (41.3 mg, 22.7 per cent) receive in the form of a white powder of 1-[1-(3-dimethylaminopropyl)piperidine-4-yl]-3-[6-(2-fluoro-4-nitrophenoxy)pyrimidine-4-yl]-1-metalmachine (135 mg), 20% palladium hydroxide on coal (50 mg), (1S)-(+)-10-camphorsulfonic acid (99 mg) and 2-(4-forfinal)acetylsalicylate.

Range1H-NMR (CDCl3) δ (ppm): 1,58-of 1.84 (6H, m)2,07 (2H, m), of 2.23 (6H, c)to 2.29 (2H, m), is 2.37 (2H, m), of 2.92 (3H, c), 3,03 (2H, m), 3,71 (2H, c), 4,18 (1H, c), 7,12 (2H, m), 7,22 (1H, m), 7,26-7,31 (3H, m), of 7.36 (2H,, m), 7,68 (1H, c), 7,86 (1H, DD, J=2,4, and 11.4 Hz), a 8.34 (1H, c), 12,38 (1H, c).

ESI-MS (m/z): 641[M+H]+.

Example of getting 221-1

tert-Butyl [1-(3-dimethylaminopropyl)piperidine-4-yl]carbamate

After addition of the hydrochloride of N,N-dimethylaminopropionic acid (1,46 g), triethylamine (1,45 ml), 1-hydroxybenzotriazole (1,93 g), and hydrochloride of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (2,19 g) to a solution of 4-(tert-butoxycarbonylamino)piperidine (1.9 g) in N,N-dimethylformamide (30 ml), the mixture is stirred for a total of 27.5 hours at room temperature in a nitrogen atmosphere. To the reaction mixture are added ethyl acetate (200 ml), saturated brine (50 ml) and 1 N. aqueous sodium hydroxide solution (50 ml) and stirred at room temperature for 30 minutes, after which the mixture is distributed. The aqueous layer was extracted with ethyl acetate. The organic layers are combined, washed 1 N. aqueous solution of hydroxide Natrii saturated salt solution, then dried over anhydrous sodium sulfate. The dried organic layer is concentrated under reduced pressure, obtaining mentioned in the title compound (2,96 g, quantitative yield) in the form of crystals of pale yellow color.

ESI-MS (m/z): 300[M+H]+.

Example of getting 221-2

N-[1-(3-Dimethylaminopropyl)piperidine-4-yl]-N-methylamine

A solution of tert-butyl [1-(3-dimethylaminopropyl)piperidine-4-yl]carbamate (2,73 g) in tetrahydrofuran (30 ml) is stirred in a bath with ice and gradually add the aluminum lithium hydride (1.04 g). The mixture is stirred under nitrogen atmosphere for 15 minutes in a bath with ice for 15 minutes at room temperature. Then it is heated under reflux for 7 hours under nitrogen atmosphere. The reaction mixture is cooled in a bath with ice, then add water (1.0 ml), 5 N. aqueous sodium hydroxide solution (1.0 ml) and water (5.0 ml) in that order, and then stirred on ice. The insoluble matter is filtered off. The filtrate is concentrated, getting mentioned in the title compound (1.51 g, 83,2%) in the form of oil pale yellow color.

Range1H-NMR (CDCl3) δ (ppm): 1,32-of 1.42 (2H, m)to 1.67 (2H, m), 1,89 (2H, m)to 1.98 (2H, m), 2,22 (6H, c), of 2.28 (2H, m), 2,32-of 2.38 (2H, m), 2,43 (3H, c), 2,90 (2H, m), 3,16-3,24 (1H, m).

ESI-MS (m/z): 200[M+H]+.

Example of getting 221-3

1-[1-(3-Dimethylaminopropyl)piperidine-4-yl]-3-[6-(2-fluoro-4-nitrophenoxy)p is rimidine-4-yl]-1-metalmachine

Specified in the title compound (135 mg, 59.1 per cent) receive in the form of a powder pale yellow color of 6-(2-fluoro-4-nitrophenoxy)pyrimidine-4-ylamine (120 mg), triethylamine (0,191 ml), phenylcarbamate (0,150 ml) and N-[1-(3-dimethylaminopropyl)piperidine-4-yl]-N-methylamine (478 mg).

Range1H-NMR (CDCl3) δ (ppm): 1,63 is 1.86 (6H, m), of 2.08 (2H, m), of 2.23 (6H, c)to 2.29 (2H, t, J=7.0 Hz), of 2.38 (2H, t, J=7.8 Hz), to 2.94 (3H, c), 3,03 (2H, m), 4,18 (1H, m), 7,40-the 7.43 (2H, m), 7,78 (1H, d, J=1.2 Hz), 8,03-to 8.14 (2H, m), with 8.33 (1H, d, J=1.2 Hz).

ESI-MS (m/z): 476[M+H]+.

Example 222

1-[1-(3-Dimethylaminopropyl)piperidine-4-yl]-3-[4-(3-fluoro-4-{3-[2-(4-forfinal)acetyl]touraid}phenoxy)pyridine-2-yl]-1-metalmachine

Specified in the title compound (51.3 mg, 22.5 percent) receive in the form of a white powder of benzyl[4-(2-{3-[1-(3-dimethylaminopropyl)piperidine-4-yl]-3-methylurea}pyridine-4-yloxy)-2-forfinal]carbamate (206 mg), 20% palladium hydroxide on coal (50 mg), (1S)-(+)-10-camphorsulfonic acid (116 mg) and 2-(4-forfinal)acetylsalicylate (0,2M solution in toluene, to 2.67 ml).

Range1H-NMR (CDCl3) δ (ppm): 1,62-of 1.85 (6H, m)2,07 (2H, m), and 2.27 (6H, c), 2,33-to 2.40 (4H, m), 2,90 (3H, c), a 3.01 (2H, m), and 3.72 (2H, c), 4,17 (1H, m), to 6.57 (1H, DD, J=2,0, 5.6 Hz), 6,92 (2H, d, J=8,8 Hz), 7,12 (2H, m,), 7,14-7,31 (4H, m), 7,74 (1H, d, J=2.0 Hz), of 8.09 (1H, d, J=5.6 Hz), with 8.33 (1H, m), 12,30 (1H, c).

ESI-MS (m/z): 640[M+H]+.

Example of getting 222-1

Benzyl [4-(2-{3-[1-(3-dimethylaminopropyl)piperidine-4-yl]-3-methylurea}pyridine-4-yloxy)-2-forfinal]carbamate

Specify the OU in the title compound (206 mg, 83,8%) are obtained in the form of oil pale yellow color of benzyl [4-(2-aminopyridine-4-yloxy)-2-forfinal]carbamate (150 mg), triethylamine (0,169 ml), phenylcarbamate (of 0.133 ml) and N-[1-(3-dimethylaminopropyl)piperidine-4-yl]-N-methylamine (424 mg).

Range1H-NMR (CDCl3) δ (ppm): 1,62-of 1.74 (6H, m), 2,02 (2H, m), 2,22 (6H, c), and 2.26-of 2.38 (4H, m), 2,89 (3H, c)of 3.00 (2H, m)to 4.16 (1H, m), 5,23 (2H, c), of 6.52 (1H, DD, J=2,4, 5,6 Hz), 6,85-of 6.90 (3H, m), 7,21 (1H, Sirs), 7,34-7,42 (5H, m), 7,68 (1H, d, J=2.4 Hz), with 8.05 (1H, d, J=5.6 Hz), 8,12 (1H, Sirs).

ESI-MS (m/z): 579[M+H]+.

Example 223

1-[1-(2-Dimethylaminoethyl)piperidine-4-yl]-3-{4-[2-fluoro-4-(3-phenylacetylamino)phenoxy]pyridine-2-yl}-1-metalmachine

Specified in the header connection (to 19.4 mg, 13.8 per cent) receive in the form of a white powder of 3-[4-(4-amino-2-pertenece)pyridine-2-yl]-1-[1-(2-dimethylaminoethyl)piperidine-4-yl]-1-metalmachine (100 mg), (1S)-(+)-10-camphorsulfonic acid (116 mg) and 2-phenylacetonitrile (0,2M solution in N,N-dimethylformamide, 1,74 ml).

Range1H-NMR (CDCl3) δ (ppm): of 1.64 (2H, m), of 1.78 (2H, m), 2,11 (2H, m), 2,28 (6H, c), 2,48 (4H, m), is 2.88 (3H, c), a 3.01 (2H, m), 3,74 (2H, c), of 4.16 (1H, m), 6,55 (1H, DD, J=2,4, 6,0 Hz), 7,17 (2H, m), 7,30 was 7.45 (6H, m), to 7.67 (1H, d, J=2.4 Hz), 7,89 (1H, DD, J=2,4, and 11.6 Hz), of 8.06 (1H, d, J=6.0 Hz), 8,69 (1H, Sirs), 12,45 (1H, c).

ESI-MS (m/z): 608[M+H]+.

Example of getting 223-1

3-[4-(2-Fluoro-4-nitrophenoxy)pyridine-2-yl]-1-[1-(2-dimethylaminoethyl)piperidine-4-yl]-1-metalmachine

Specified in the title compound (296 mg, 80,0%) is obtained from 4-(2-FPO is-4-nitrophenoxy)pyridine-2-ylamine (200 mg), triethylamine (0,252 ml), phenylcarbamate (0,252 ml) and N-[1-(2-dimethylaminoethyl)piperidine-4-yl]-N-methylamine (595 mg).

Range1H-NMR (CDCl3) δ (ppm): 1,63 (2H, m)to 1.79 (2H, m), 2,10 (2H, m), and 2.26 (6H, c), 2,47 (4H, m), is 2.88 (3H, c), a 3.01 (2H, m), 4,14 (1H, m), of 6.65 (1H, DD, J=2,4, 5,6 Hz), 7.23 percent (1H, Sirs), 7,30 (1H, m), of 7.75 (1H, d, J=2,4 Hz), 8,11 (2H, m), 8,16 (1H, d, J=5.6 Hz).

ESI-MS (m/z): 461[M+H]+.

Example of getting 223-2

3-[4-(4-Amino-2-pertenece)pyridine-2-yl]-1-[1-(2-dimethylaminoethyl)piperidine-4-yl]-1-metalmachine

Specified in the title compound (260 mg, 93.9 per cent) receive in the form of a yellow oil from 3-[4-(2-fluoro-4-nitrophenoxy)pyridine-2-yl]-1-[1-(2-dimethylaminoethyl)piperidine-4-yl]-1-metalmachine (296 mg) and 20% palladium hydroxide on coal (70 mg).

Range1H-NMR (CDCl3) δ (ppm): 1,63 (2H, m), 1,72-to 1.82 (2H, m), 2,10 (2H, m), and 2.26 (6H, c), 2,27-of 2.50 (4H, m), 2,85 (3H, c)of 3.00 (2H, m in), 3.75 (2H, Sirs), is 4.15 (1H, m), 6.42 per-of 6.45 (1H, m), 6.48 in-6,53 (2H, m), to 6.95 (1H, m), 7,21 (1H, m), of 7.64 (1H, d, J=2.4 Hz), 8,02 (1H, d, J=6.0 Hz).

ESI-MS (m/z): 431[M+H]+.

Example 224

1-[1-(2-Dimethylaminoethyl)piperidine-4-yl]-3-[4-(2-fluoro-4-{3-[2-(4-forfinal)acetyl]touraid}phenoxy)pyridine-2-yl]-1-metalmachine

Specified in the title compound (19.2 mg, 13.2 per cent) receive in the form of a white powder of 3-[4-(4-amino-2-pertenece)pyridine-2-yl]-1-[1-(2-dimethylaminoethyl)piperidine-4-yl]-1-metalmachine (100 mg), (1S)-(+)-10-camphorsulfonic acid (116 mg) and 2-(4-forfinal)acetylsalicylate.

Range1H-NMR (CDCl3) #x003B4; (ppm): of 1.65 (2H, m), 1,72-1,90 (2H, m), and 2.14 (2H, m), a 2.36 (6H, c)to 2.54 (4H, m), is 2.88 (3H, c), 3,03 (2H, m), and 3.72 (2H, c), 4,18 (1H, m), 6,55 (1H, DD, J=2,4, 6,0 Hz), 7,10 and 7.36 (7H, m), to 7.67 (1H, d, J=the 2.4 Hz), 7,89 (1H, DD, J=2,4, and 11.6 Hz), of 8.06 (1H, d, J=6.0 Hz), to 8.57 (1H, Sirs), 12,40 (1H, c).

ESI-MS (m/z): 626[M+H]+.

Example 225

1-[1-(3-Dimethylaminopropyl)piperidine-4-yl]-3-[4-(2-fluoro-4-{3-[2-(4-forfinal)acetyl]touraid}phenoxy)pyridine-2-yl]-1-metalmachine

Specified in the header connection (12,8 mg) are obtained in the form of a white powder of crude 3-[4-(4-amino-2-pertenece)pyridine-2-yl]-1-[1-(3-dimethylaminopropyl)piperidine-4-yl]-1-metalmachine (102 mg), (1S)-(+)-10-camphorsulfonic acid (90,4 mg) and 2-(4-forfinal)acetylsalicylate (1,83 ml, 0,25M solution in toluene).

Range1H-NMR (CDCl3) δ (ppm): 1,67 (2H, m), 1,83-of 1.93 (4H, m), and 2.14 (2H, m), 2,43 (6H, c)to 2.46 (2H, m), 2.57 m (2H, m), 2,89 (3H, c), 3,05 (2H, m), of 3.73 (2H, c), 4,19 (1H, m), 6,55 (1H, DD, J=2,4, 6,0 Hz), 7,10-7,20 (4H, m), 7,27-to 7.35 (4H, m), of 7.64 (1H, d, J=2.4 Hz), of 7.90 (1H, DD, J=2,4, and 11.6 Hz), of 8.06 (1H, d, J=6.0 Hz), 12,41 (1H, c).

ESI-MS (m/z): 640[M+H]+.

Example of getting 225-1

3-[4-(2-Fluoro-4-nitrophenoxy)pyridine-2-yl]-1-[1-(3-dimethylaminopropyl)piperidine-4-yl]-1-metalmachine

Specified in the title compound (226 mg, 59.3%) were receiving in the form of a white powder from 4-(2-fluoro-4-nitrophenoxy)pyridine-2-ylamine (200 mg), triethylamine (0,252 ml), phenylcarbamate (0,252 ml) and N-[1-(3-dimethylaminopropyl)piperidine-4-yl]-N-methylamine (595 mg).

Range1H-NMR (CDCl3) δ (ppm): 1,60-1,84 (H, m), is 2.05 (2H, m), and 2.26 (6H, c)to 2.35 (4H, m), 2,90 (3H, c), a 3.01 (2H, m), is 4.15 (1H, m), of 6.65 (1H, DD, J=2,4, 5,6 Hz), 7,25 (1H, Sirs), 7,30 (1H, m), of 7.75 (1H, d, J=2.4 Hz), 8,11 (2H, m), 8,16 (1H, d, J=5,6 Hz).

ESI-MS (m/z): 475[M+H]+.

Example of getting 225-2

3-[4-(4-Amino-2-pertenece)pyridine-2-yl]-1-[1-(3-dimethylaminopropyl)piperidine-4-yl]-1-metalmachine

Specified in the title compound (205 mg, 96.8 per cent) receive in the form of oil is pale-yellow 3-[4-(2-fluoro-4-nitrophenoxy)pyridine-2-yl]-1-[1-(3-dimethylaminopropyl)piperidine-4-yl]-1-metalmachine (226 mg) and 20% palladium hydroxide on coal (70 mg).

Range1H-NMR (CDCl3) δ (ppm): 1,64-of 1.78 (4H, m), is 2.05 (2H, m), of 2.25 (6H, c), 2,31-of 2.38 (4H, m), is 2.88 (3H, c)of 3.00 (2H, m in), 3.75 (2H, m)to 4.16 (1H, m), of 6.49-6,52 (3H, m), to 6.95 (1H, m), 7,27 (1H, m), of 7.64 (1H, d, J=2.0 Hz), 8,01 (1H, d, J=5.6 Hz).

ESI-MS (m/z): 445[M+H]+.

Example 226

4-(2-Dimethylaminoethyl)-[1,4]diazepan-1-carboxylic acid [6-(2-fluoro-4-{3-[2-(4-forfinal)acetyl]touraid}phenoxy)pyrimidine-4-yl]amide

Specified in the title compound (20.5 mg, 20.4 percent) receive in the form of a white powder of crude 4-(2-dimethylaminoethyl)-[1,4]diazepan-1-carboxylic acid [6-(4-amino-2-pertenece)pyrimidine-4-yl]amide (68.6 mg)synthesized from 4-(2-dimethylaminoethyl)-[1,4]diazepan-1-carboxylic acid [6-(2-fluoro-4-nitrophenoxy)pyrimidine-4-yl]amide (144 mg), D-10-camphorsulfonic acid (76,4 mg) and 0,25M solution of 2-(4-forfinal)acetylsalicylate in toluene (1.31 ml).

Range1H-NMR (CDCl3

ESI-MS (m/z): 613[M+H]+.

Example of getting 226-1

Trihydrochloride (2-[1,4]diazepan-1-retil)dimethylamine

After adding N,N-dimethylformamide (20 ml) to benzyl ether [1,4]diazepan-1-carboxylic acid (2 ml) in nitrogen atmosphere, at room temperature, add the potassium carbonate in (6.67 g) and 2-dimethylaminoethanol (1,67 g). The reaction mixture is heated to 70°C and stirred for 2 hours. Then heat it up to 80°C and stirred for 1 hour. Add another portion of 2-diethylaminoethylamine (420 mg) and the reaction mixture is stirred for 2 hours. Then the reaction mixture is cooled to room temperature. After which it is distributed between ethyl acetate (100 ml) and saturated aqueous ammonium chloride (50 ml). The organic layer is separated and washed with saturated aqueous ammonium chloride (50 ml), water (50 ml) and saturated saline (50 ml) in that order and then dried over anhydrous sodium sulfate. The solvent is distilled off under reduced pressure and the resulting residue is purified column chromatography on silica gel (FUJI SILYSIA NH, eluent: heptane:ethyl acetate = 4:1). The fractions containing the target compound, concentrate in on what igenom pressure, receiving the crude benzyl ether of 4-(2-dimethylaminoethyl)-[1,4]diazepan-1-carboxylic acid (724 mg, 24.5 per cent) in the form of oil pale yellow color.

After adding methanol (72 ml) to the crude product (724 mg) is added 20% palladium hydroxide (1.07 g) in a nitrogen atmosphere and the mixture is stirred for 4 hours using the apparatus for hydrogenation under pressure. After replacing the atmosphere in the reaction vessel by nitrogen, the catalyst is filtered off. Then it is washed with methanol and the filtrate concentrated. To the residue is added 4 n hydrochloric acid in ethyl acetate (4,15 ml) and the mixture is stirred. Excess hydrochloric acid is distilled off by stirring under reduced pressure. The solvent is distilled off under reduced pressure, and the residue is dried under reduced pressure and get listed in the title compound (660 mg, 99,2%) as a solid brown color.

ESI-MS (m/z): 172[M+H]+.

Example of getting 226-2

4-(2-Dimethylaminoethyl)-[1,4]diazepan-1-carboxylic acid [6-(2-fluoro-4-nitrophenoxy)pyrimidine-4-yl]amide

Specified in the title compound (144 mg, 80.3 per cent) receive in the form of oil is pale-yellow 6-(2-fluoro-4-nitrophenoxy)pyrimidine-4-ylamine (100 mg), tetrahydrofuran (4 ml), phenylcarbamate (0,151 ml), trihydrochloride (2-[1,4]diazepan-1-retil)dimethylamine (337 mg) and triethylamine (0,167 ml).

ESI-MS (m/z): 448[M+H]+.

Example 227

1-[1-(3-Dimethylaminopropyl)piperidine-4-yl]-3-[4-(4-{3-[2-(4-forfinal)acetyl]touraid}phenoxy)pyridine-2-yl]-1-metalmachine

Specified in the header connection (26,4 mg, 17.4 per cent) receive in the form of a white powder of 3-[4-(4-aminophenoxy)pyridine-2-yl]-1-[1-(3-dimethylaminopropyl)piperidine-4-yl]-1-metalmachine (104 mg), (1S)-(+)-10-camphorsulfonic acid (96,4 mg) and 2-(4-forfinal)acetylsalicylate (1,95 ml, 0,25M solution in toluene).

Range1H-NMR (CDCl3) δ (ppm): 1,62-of 1.94 (6H, m), is 2.05 (2H, m), and 2.26 (6H, c)to 2.35 (4H, m), 2,89 (3H, c)of 3.00 (2H, m), 3,71 (2H, c), is 4.15 (1H, m), 6,55 (1H, DD, J=2,0, 5.6 Hz), 7,09-7,13 (4H, m), 7,18 (1H, c), 7,26-7,31 (3H, m), to 7.67-of 7.69 (3H, m), of 8.06 (1H, d, J=5.6 Hz), to 12.28 (1H, c).

ESI-MS (m/z): 622[M+H]+.

Example of getting 227-1

1-[1-(3-Dimethylaminopropyl)piperidine-4-yl]-1-methyl-3-[4-(4-nitrophenoxy)pyridine-2-yl]urea

Specified in the title compound (140 mg, 76.7 percent) receive in the form of oil is pale-yellow 4-(4-nitrophenoxy)pyridine-2-ylamine (92,5 mg), triethylamine (0,167 ml), phenylcarbamate (of) 0.157 ml) and N-[1-(3-dimethylaminopropyl)piperidine-4-yl]-N-methylamine (319 mg).

Range1H-NMR (CDCl3) δ (ppm): 1,62-of 1.80 (6H, m), 2,04 (2H, m), 2,22 (6H, c), and 2.26-2,31 (2H, m), 2,34-2,39 (2H, m), 2,90 (3H, c)of 3.00 (2H, m), is 4.15 (1H, m), of 6.65 (1H, DD, J=2,4, 6,0 Hz), 7,19 (2H, d, J=9.0 Hz), 7,25 (1H, Sirs), 7,81 (1H, d, J=2.4 Hz), 8,17 (1H, d, J=6.0 Hz), of 8.27 (2H, d, J=9.0 Hz).

ESI-MS (m/z): 457[M+H]+.

Example of getting 227-2

3-[4-(4-Aminophenoxy)pyridine-2-the l]-1-[1-(3-dimethylaminopropyl)piperidine-4-yl]-1-metalmachine

Specified in the title compound (104 mg, 79.4 per cent) receive in the form of oil pale yellow color of 1-[1-(3-dimethylaminopropyl)piperidine-4-yl]-1-methyl-3-[4-(4-nitrophenoxy)pyridine-2-yl]urea (140 mg) and 10% palladium on coal (100 mg).

Range1H-NMR (CDCl3) δ (ppm): 1,64-to 1.82 (6H, m)to 2.06 (2H, m), 2,62 (6H, c), 2,32-to 2.40 (4H, m), 2,71 (2H, Sirs), is 2.88 (3H, c), a 3.01 (2H, m), 4,17 (1H, m), 6.48 in (1H, DD, J=2.0 a, 6,0 Hz), 6,70 (2H, d, J=8,8 Hz), make 6.90 (2H, d, J=8,8 Hz), 7,25 (1H, Sirs), a 7.62 (1H, d, J=2.0 Hz), 7,98 (1H, d, J=6.0 Hz).

ESI-MS (m/z): 427[M+H]+.

Example 228

3-[6-(4-{3-[2-(4-Forfinal)acetyl]touraid}phenoxy)pyrimidine-4-yl]-1-methyl-1-(1-methylpiperidin-4-yl)urea

Specified in the header connection (46,3 mg, 23%) are obtained as white crystals from 3-[6-(4-aminophenoxy)pyrimidine-4-yl]-1-methyl-1-(1-methylpiperidin-4-yl)urea (131 mg), (+)-10-camphorsulfonic acid (81 mg) and a solution of 2-(4-forfinal)acetylsalicylate in toluene (0,25M, 3.0 ml).

Range1H-NMR (CDCl3) δ (ppm): 1,60-2,00 (4H, m), 2,10-of 2.20 (2H, m), 2,33 (3H, c), 2,90 was 3.05 (5H, m), 3,71 (2H, c), is 4.21 (1H, m), 7,10-to 7.35 (7H, m), to 7.59 (1H, d, J=0.8 Hz), 7,69-7,74 (2H, m), of 8.37 (1H, d, J=0.8 Hz), 8,44 (1H, Sirs), 12,27 (1H, Sirs).

ESI-MS (m/z): 552[M+H]+.

Example of getting 228-1

1-Methyl-1-(1-methylpiperidin-4-yl)-3-[6-(4-nitrophenoxy)pyrimidine-4-yl]urea

Specified in the title compound (160 mg, 96%) was obtained as colorless oil from 1-methyl-4-(methylamino)piperidine (331 mg), 4-amino-6-(4-nitrophenoxy)pyrimidine (100 mg), Treaty the amine (0,150 ml) and phenylcarbamate (is 0.135 ml).

Range1H-NMR (CDCl3) δ (ppm): 1,60-2,00 (4H, m), 2,09-of 2.16 (2H, m), 2,32 (3H, c), 2,80-3,00 (5H, m), 4,20 (1H, m), 7,29-7,38 (3H, m), of 7.70 (1H, d, J=0.8 Hz), 8,14-of 8.33 (2H, m), 8,39 (1H, d, J=0.8 Hz).

Example of getting 228-2

3-[6-(4-Aminophenoxy)pyrimidine-4-yl]-1-methyl-1-(1-methylpiperidin-4-yl)urea

Specified in the title compound (132 mg, 90%) are obtained in the form of a white powder of 1-methyl-1-(1-methylpiperidin-4-yl)-3-[6-(4-nitrophenoxy)pyrimidine-4-yl]urea (160 mg) and 20% palladium hydroxide on coal (120 mg).

ESI-MS (m/z): 357[M+H]+.

Example 229

4-{[4-(Dimethylaminomethyl)piperidine-1-yl]carbylamine}-6-(4-{3-[2-(4-forfinal)acetyl]touraid}phenoxy)pyrimidine

Specified in the title compound (46 mg, 25%) are obtained as white powder from 4-(4-aminophenoxy)-6-{[4-(dimethylaminomethyl)piperidine-1-yl]carbylamine}pyrimidine (120 mg), (+)-10-camphorsulfonic acid (71,5 mg) and a solution of 2-(4-forfinal)acetylsalicylate in toluene (0,25M, and 2.6 ml).

Range1H-NMR (CDCl3) δ (ppm): 1,10-1,30 (2H, m)of 1.75 (1H, m), 1,80-2,00 (2H, m), 2,10-of 2.45 (8H, m), 2,85-of 3.00 (2H, m), 3,71 (2H, c), 4,00-4,20 (2H, m), 7,10-to 7.35 (7H, m), 7,54 (1H, d, J=0.8 Hz), 7,69-7,73 (2H, m), at 8.36 (1H, d, J=0.8 Hz), 8,44 (1H, Sirs), 12,27 (1H, Sirs).

ESI-MS (m/z): 566[M+H]+.

Example of getting 229-1

4-{[4-(Dimethylaminomethyl)piperidine-1-yl]carbylamine}-6-(4-nitrophenoxy)pyrimidine

Specified in the title compound (137 mg, 79%) was obtained as crystals pale yellow color of 4-amino-6-(4-what icrofinance)pyrimidine (100 mg), phenylcarbamate (is 0.135 ml), dihydrochloride 4-(dimethylaminomethyl)piperidine (464 mg) and triethylamine (1,06 ml).

Range1H-NMR (CDCl3) δ (ppm): 1,10-1,30 (2H, m)of 1.73 (1H, m), 1,80-1,90 (2H, m), 2,10-of 2.20 (2H, m), 2,24 (6H, c), 2,80-3,00 (2H, m), 4,00-4,20 (2H, m), 7,29-7,33 (2H, m), 7,39 (1H, Sirs), to 7.67 (1H, d, J=0.8 Hz), 8,28-8,33 (2H, m), scored 8.38 (1H, d, J=0.8 Hz).

Example of getting 229-2

4-(4-Aminophenoxy)-6-{[4-(dimethylaminomethyl)piperidine-1-yl]carbylamine}pyrimidine

Specified in the title compound (120 mg, 95%) are obtained as white powder from 4-{[4-(dimethylaminomethyl)piperidine-1-yl]carbylamine}-6-(4-nitrophenoxy)pyrimidine (137 mg) and 20% palladium hydroxide on coal (100 mg).

ESI-MS (m/z): 371[M+H]+.

Example 230

4-(4-{3-[2-(4-Forfinal)acetyl]touraid}phenoxy)-6-{[4-(1-methylpiperazin-4-yl)piperidine-1-yl]carbylamine}pyrimidine

Specified in the header of the connection (of 45.3 mg, 23%) are obtained as white powder from 4-(4-aminophenoxy)-6-{[4-(1-methylpiperazin-4-yl)piperidine-1-yl]carbylamine}pyrimidine (133 mg), (+)-10-camphorsulfonic acid (135 mg) and a solution of 2-(4-forfinal)acetylsalicylate in toluene (0,25M, and 2.6 ml).

Range1H-NMR (CDCl3) δ (ppm): 1,40-2,00 (5H, m), 2,33 (3H, c), 2,40-of 3.00 (10H, m), 3,71 (2H, c), 4,05-4,20 (2H, m), 7,10-7,40 (7H, m), 7,54 (1H, d, J=0.8 Hz), 7,69-7,73 (2H, m), of 8.37 (1H, d, J=0.8 Hz), to 8.45 (1H, Sirs), 12,27 (1H, Sirs).

ESI-MS (m/z): 607[M+H]+.

Example of getting 230-1

4-{[4-(1-Methylpiperazin-4-yl)piperidine-1-yl]CARBONYLS is but}-6-(4-nitrophenoxy)pyrimidine

Specified in the title compound (148 mg, 78%) are obtained in the form of oil is pale-yellow 4-amino-6-(4-nitrophenoxy)pyrimidine (100 mg), triethylamine (0,150 ml), phenylcarbamate (is 0.135 ml) and 4-(1-methylpiperazin-4-yl)piperidine (400 mg).

Range1H-NMR (CDCl3) δ (ppm): 1,40-2,00 (5H, m), 2,31 (3H, c), 2,40-of 3.00 (10H, m), 4,00-4,20 (2H, m), 7,27-7,33 (2H, m), 7,41 (1H, Sirs), the 7.65 (1H, d, J=0.8 Hz), 8,29-8,32 (2H, m), scored 8.38 (1H, d, J=0.8 Hz).

Example of getting 230-2

4-(4-Aminophenoxy)-6-{[4-(1-methylpiperazin-4-yl)piperidine-1-yl]carbylamine}pyrimidine

Specified in the title compound (133 mg, 97%) are obtained in the form of a powder pale yellow 4-{[4-(1-methylpiperazin-4-yl)piperidine-1-yl]carbylamine}-6-(4-nitrophenoxy)pyrimidine (148 mg) and 20% palladium hydroxide on coal (100 mg).

ESI-MS (m/z): 412[M+H]+.

Example 231

4-(4-{3-[2-(4-Forfinal)acetyl]touraid}phenoxy)-6-{[4-(1-methylpiperidin-4-yl)piperazine-1-yl]carbylamine}pyrimidine

Specified in the header of the connection (by 44.3 mg, 23%) are obtained as white powder from 4-(4-aminophenoxy)-6-{[4-(1-methylpiperidin-4-yl)piperazine-1-yl]carbylamine}pyrimidine (131 mg), (+)-10-camphorsulfonic acid (133 mg) and a solution of 2-(4-forfinal)acetylsalicylate in toluene (0,25M, and 2.6 ml).

Range1H-NMR (CDCl3) δ (ppm): 1,50-2,00 (6H, m), 2.26 and-a 2.36 (4H, m), 2,54-of 2.64 (4H, m), 2,90 totaling 3.04 (2H, m), 3,48 of 3.56 (4H, m), 3,71 (2H, c), 7,10-to 7.35 (7H, m), 7,54 (1H, d, J=0.8 Hz), 7,69-7,73 (2H, m), of 8.37 (1H, d, J=0,8 Hz), 8,44 (1H, Sirs), 12,27 (H, Sirs).

ESI-MS (m/z): 607[M+H]+.

Example of getting 231-1

4-{[4-(1-Methylpiperidin-4-yl)piperazine-1-yl]carbylamine}-6-(4-nitrophenoxy)pyrimidine

Specified in the title compound (142 mg, 75%) are obtained in the form of oil is pale-yellow 4-amino-6-(4-nitrophenoxy)pyrimidine (100 mg), triethylamine (0,150 ml), phenylcarbamate (is 0.135 ml) and 4-(1-methylpiperidin-4-yl)piperazine (452 mg).

Range1H-NMR (CDCl3) δ (ppm): 1,60-2,00 (6H, m), 2,20-2,40 (4H, m), 2,50-2,70 (4H, m), 2,80-3,00 (2H, m), 3,40-of 3.60 (4H, m), 7,29-7,34 (2H, m), 7,37 (1H, Sirs), 7,66 (1H, d, J=0.8 Hz), 8,28-of 8.33 (2H, m), scored 8.38 (1H, d, J=0,8 Hz).

Example of getting 231-2

4-(4-Aminophenoxy)-6-{[4-(1-methylpiperidin-4-yl)piperazine-1-yl]carbylamine}pyrimidine

Specified in the title compound (131 mg, 99%) are obtained in the form of a powder pale yellow 4-{[4-(1-methylpiperidin-4-yl)piperazine-1-yl]carbylamine}-6-(4-nitrophenoxy)pyrimidine (142 mg) and 20% palladium hydroxide on coal (100 mg).

ESI-MS (m/z): 412[M+H]+.

Example 232

N-(3-Fluoro-4-{2-[3-(1-methylpiperidin-4-yl)ureido]pyridine-4-yloxy}phenyl)-N'-(4-forfinal)malonamide

Range1H-NMR (CDCl3) δ (ppm): 1,50-2,07 (4H, m), 2,24 (2H, m), 2,32 (3H, c), was 2.76 (2H, m), 3,63 (2H, c), 3,81 (1H, m), 6,27 (1H, m), of 6.66 (1H, DD, J=1,2, 6,0 Hz), 7,01 (2H, m), 7,14 (1H, m), 7,28 (1H, m), 7,54 (2H, m,), to 7.67 (1H, m), with 8.05 (1H, d, J=6.0 Hz), 8,35 (1H, Sirs), a 9.35 (1H, Sirs), 9,72 (2H, m).

ESI-MS (m/z): 539[M+H]+.

Example 233

N-(4-{2-[(4-Dimethylaminopyridine-1-carbonyl)amino]pyridine-4-ilok and}-3-forfinal)-N'-(4-forfinal)malonamide

Range1H-NMR (CDCl3) δ (ppm): to 1.45 (2H, m)to 1.86 (2H, m), 2,28 (6H, c), of 2.34 (1H, m), 2,90 (2H, m), 3,49 (2H, c), 4,07 (2H, m), 6,59 (1H, DD, J=2,4, 6,0 Hz), 7,03 (2H, m), 7,13 (1H, m), 7,16-7,40 (2H, m), 7,45-7,60 (3H, m), of 7.70 (1H, DD, J=2,4, 12.0 Hz), of 8.06 (1H, d, J=6.0 Hz), 8,68 (1H, Sirs), 9,24 (1H, c).

ESI-MS (m/z): 553[M+H]+.

Example 234

4-{2-Fluoro-4-[3-(2-phenylacetyl)ureido]phenoxy}-2-[(4-oxopiperidin-1-yl)carbylamine]pyridine

Range1H-NMR (CDCl3) δ (ppm): 2,40-2,60 (4H, m), 3,76 (2H, c), 3,76-a 3.83 (4H, m), is 6.54 (1H, m), 7,00-the 7.65 (11H, m), of 8.04 (1H, m), of 10.58 (1H, c).

ESI-MS (m/z): 528[M+Na]+.

Example of getting 234-1

4-(2-Fluoro-4-nitrophenoxy)-2-[(4-oxopiperidin-1-yl)carbylamine]pyridine

Range1H-NMR (CDCl3) δ (ppm): 2,40-2,70 (4H, m), 3,70-are 3.90 (4H, m), to 6.67 (1H, DD, J=2,4, 5,6 Hz), 7,33 (1H, m), of 7.48 (1H, Sirs), 7,73 (1H, d, J=2.4 Hz), 8,10-8,30 (3H, m).

Example of getting 234-2

4-(4-Amino-2-pertenece)-2-[(4-oxopiperidin-1-yl)carbylamine]pyridine

Range1H-NMR (CDCl3) δ (ppm): 2,50-2,60 (4H, m), 3,76 (2H, Sirs), 3,79-a 3.83 (4H, m), of 6.45 (1H, DD, J=2,4, 5,6 Hz), 6,50-of 6.52 (1H, m), 6.90 to-7,00 (1H, m), the 7.43 (1H, W), to 7.61 (1H, Sirs), 8,03 (1H, m).

Example 235

2-{[4-(dimethylamino)piperidine-1-yl]carbylamine}-4-{2-fluoro-4-[3-(2-phenylacetyl)ureido]phenoxy}pyridine

Range1H-NMR (CDCl3) δ (ppm): 1,40-1,60 (2H, m), 1,80-2,00 (2H, m), 2,28 (6H, c)to 2.35 (1H, m), 2,80-3,00 (2H, m in), 3.75 (2H, c), 4,00-4,20 (2H, m), 6,53 (1H, m), 7,10-7,69 (10H, m), of 7.70 (1H, c), of 8.04 (1H, d, J=5.6 Hz), 10,57 (1H, c).

ESI-MS (m/z): 535[M+H]+.

Example 236

2-{[4-(Azetidin-1-yl)piperidine-1-yl]ka is Beniamino}-4-{2-fluoro-4-[3-(2-phenylacetyl)ureido]phenoxy}pyridine

Range1H-NMR (CDCl3) δ (ppm): 1,20-of 1.35 (2H, m), 1,60-1,80 (2H, m), 2.00 in of 2.10 (2H, m), of 2.20 (1H, m), 2.95 and was 3.05 (2H, m), of 3.10-3.20 (4H, m in), 3.75 (2H, c), 3,80-of 3.95 (2H, m), of 6.52 (1H, m), 7,05 was 7.45 (8H, m), 7,55-the 7.65 (2H, m,), 8,02 (1H, d, J=5.6 Hz), 8,11 (1H, c), or 10.60 (1H, c).

ESI-MS (m/z): 547[M+H]+.

Example 237

4-Dimethylaminopyridine-1-carboxylic acid {6-[2-fluoro-4-(3-phenylacetylamino)phenoxy]pyrimidine-4-yl}amide

Range1H-NMR (CDCl3) δ (ppm): 1,50 (2H, m), at 1.91 (2H, m), is 2.30 (6H, c)2,39 (1H, m), 2,96 (2H, m), 3,74 (2H, c), of 4.12 (2H, m), 7,21 (1H, m), 7,28-to 7.32 (2H, m), 7,32-of 7.48 (5H, m), 7,63 (1H, m), 7,86 (1H, DD, J=2,4, the 11.6 Hz), with 8.33 (1H, m), 8,40 (1H, Sirs), 12,42 (1H, Sirs).

ESI-MS (m/z): 552[M+H]+.

Example of getting 237-1

4-Dimethylaminopyridine-1-carboxylic acid [6-(4-amino-2-pertenece)pyrimidine-4-yl]amide

Range1H-NMR (CDCl3) δ (ppm): 1,49 (2H, m), 1,90 (2H, m), is 2.30 (6H, m), is 2.37 (1H, m), 2,95 (2H, m), of 3.73 (2H, Sirs), 4,11 (2H, m), 6,45 (1H, m), 6,50 (1H, m), 6,97 (1H, m), 7,32 (1H, Sirs), 7,56 (1H, c), of 8.37 (1H, c).

ESI-MS (m/z): 375[M+H]+.

Example 238

N-(2-Fluoro-4-{2-[3-(1-methylpiperidin-4-yl)ureido]pyridine-4-yloxy}phenyl)-N'-(4-forfinal)malonamide

Range1H-NMR (DMSO-d6) δ (ppm): 1,34-of 1.44 (2H, m), of 1.78 (2H, m), 2,03 (2H, m), of 2.15 (3H, c), 2,58 (2H, m), of 3.48 (1H, m)to 3.58 (2H, m), to 6.57 (1H, DD, J=2,4, 6,0 Hz), 7,01 (2H, m), 7,17 (2H, m), 7,25 (1H, DD, J=2,4, 7,6 Hz), 7,63 (2H, DD, J=5.0 and 8.6 Hz), to $ 7.91 (1H, m), of 8.04 (1H, m), of 8.09 (1H, d, J=6.0 Hz), 9,03 (1H, c), 10,11 (1H, c), of 11.26 (1H, c).

ESI-MS (m/z): 539[M+H]+.

Example 239

N-[4-(2-{[4-(Azetidin-1-yl)piperidine-1-carbonyl]amino}pyridine-4-yloxy)-2-FPO the phenyl]-N'-(4-forfinal)malonamide

Range1H-NMR (DMSO-d6) δ (ppm): 1,06 (2H, m)of 1.55 (2H, m), 1,90 (2H, m), 2,12 (1H, m), 2,98 (2H, m), 3,05 (4H, m)to 3.58 (2H, c), with 3.79 (2H, m), 6,60 (1H, DD, J=2,0, 5.6 Hz), 7,00 (1H, m), 7,17 (2H, m), 7,24 (1H, DD, J=2,6, 7,4 Hz), 7,40 (1H, d, J=2.0 Hz), 7,63 (2H, DD, J=5,4, 9,2 Hz), 8,03 (1H, m)to 8.12 (1H, d, J=5,2 Hz), 9,17 (1H, c), 10,10 (1H, c), of 10.25 (1H, c).

ESI-MS (m/z): 565[M+H]+.

Example 240

N-(4-{2-[(4-Dimethylaminopyridine-1-carbonyl)amino]pyridine-4-yloxy}-2-forfinal)-N'-(4-forfinal)malonamide

Range1H-NMR (DMSO-d6) δ (ppm): of 1.18 to 1.31 (2H, m), 1,72 (2H, m), of 2.15 (6H, c)of 2.23 (1H, m)of 2.75 (2H, m)to 3.58 (2H, c), 4.09 to (2H, m), 6,60 (1H, DD, J=2.0 a, 5,2 Hz), 7,01 (1H, m), 7,17 (2H, m), 7,24 (1H, DD, J=2,8, 7,6 Hz), 7,40 (1H, d, J=2.0 Hz), 7,63 (2H, DD, J=5.0 and 9.0 Hz), 8,03 (1H, m), 8,13 (1H, d, J=5,2 Hz), of 9.21 (1H, c), 10,10 (1H, c), of 10.25 (1H, c).

ESI-MS (m/z): 553[M+H]+.

Example 241

4-Dimethylaminopyridine-1-carboxylic acid {6-[2-fluoro-4-(3-phenylacetylamino)phenoxy]pyrimidine-4-yl}amide

Range1H-NMR (CDCl3) δ (ppm): 1,40-of 1.78 (2H, m), with 1.92 (2H, m), 2,33 (6H, Sirs), 2,30-2,52 (1H, m), 2,96 (2H, m in), 3.75 (2H, c), of 4.13 (2H, m), 7,10-7,20 (2H, m), 7,29 (2H, m), 7,32-7,46 (4H, m), 7,55-7,66 (3H, m), a 8.34 (1H, c), 10,55 (1H, Sirs).

ESI-MS (m/z): 536[M+H]+.

Example 242

4-(Azetidin-1-yl)piperidine-1-carboxylic acid {6-[2-fluoro-4-(3-phenylacetylamino)phenoxy]pyrimidine-4-yl}amide

Range1H-NMR (CDCl3) δ (ppm): 1,32 (2H, m)of 1.73 (2H, m)2,07 (2H, m), 2,24 (1H, m), 3,11 (2H, m), 3,19 (4H, m in), 3.75 (2H, c), with 3.89 (2H, m), to 7.15 (2H, m), 7,22-7,46 (6H, m), 7,58-the 7.65 (2H, m), 7,80 (1H, Sirs), with 8.33 (1H, m), 10,57 (1H, Sirs).

ESI-MS (m/z): 548[M+H]+.

Example 43

4-(Azetidin-1-yl)piperidine-1-carboxylic acid {4-[3-fluoro-4-(3-phenylacetylamino)phenoxy]pyridine-2-yl}amide

Range1H-NMR (CD3OD) δ (ppm): 1,15 (2H, m), of 1.78 (2H, m), is 2.09 (2H, m), of 2.34 (1H, m), 2,90 (2H, m), and 3.31 (4H, m), and 3.72 (2H, c), 4,08 (2H, m), 6,60 (1H, DD, J=2,0, 5.8 Hz), to 6.95 (1H, m),? 7.04 baby mortality (1H, DD, J=2,8, and 11.6 Hz), 7,26 and 7.36 (6H, m), 8,08 (1H, d, J=5.8 Hz), to 8.20 (1H, m).

ESI-MS (m/z): 547[M+H]+.

Example 244

4-Dimethylaminopyridine-1-carboxylic acid {4-[3-fluoro-4-(3-phenylacetylamino)phenoxy]pyridine-2-yl}amide

Range1H-NMR (CD3OD) δ (ppm): 1,40 (2H, m), with 1.92 (2H, m), is 2.30 (6H, c), 2,43 (1H, m), 2,87 (2H, m), and 3.72 (2H, c), 4,18 (2H, m), is 6.61 (1H, DD, J=2,4, 5.8 Hz), to 6.95 (1H, m),? 7.04 baby mortality (1H, DD, J=2,4, 11.2 Hz), 7,26 and 7.36 (6H, m), of 8.09 (1H, d, J=5.8 Hz), 8,21 (1H, m).

ESI-MS (m/z): 535[M+H]+.

Example 245

2-{[(3R)-3-Dimethylaminopropan-1-yl]carbylamine}-4-{2-fluoro-4-[3-(2-phenylacetyl)touraid]phenoxy}pyridine

Range1H-NMR (CDCl3) δ (ppm): to 1.86 (1H, m), 2,17 (1H, m), and 2.27 (6H, c)to 2.74 (1H, m), 3,21 (1H, m)to 3.41 (1H, m), the 3.65 (1H, m), 3,70-of 3.80 (1H, m), 3,74 (2H, c), 6,56 (1H, DD, J=2,4, 5,6 Hz), 7,00 (1H, c), 7,18 (1H, m,), 7,30-7,47 (6H, m), of 7.69 (1H, d, J=2.4 Hz), 7,89 (1H, DD, J=2,4, 12.0 Hz), with 8.05 (1H, d, J=5.6 Hz), 8,49 (1H, Sirs), to 12.44 (1H, c).

ESI-MS (m/z): 537[M+H]+.

Example of getting 245-1

2-{[(3R)-3-Dimethylaminopropan-1-yl]carbylamine}-4-(2-fluoro-4-nitrophenoxy)pyridine

Range1H-NMR (CDCl3) δ (ppm): 1,91 (1H, m), 2,19 (1H, m), 2,28 (6H, c), was 2.76 (1H, m), 3,23 (1H, m)to 3.41 (1H, m), 3,60-of 3.80 (2H, m), to 6.67 (1H, DD, J=2,4, 5,6 Hz), 6,83 (1H, m), 7,10 (1H, Sirs), 7,78 (1H, d, J=2.4 Hz), 8,09-8,17 (3H, m).

4-(4-Amino-2-pertenece)-2-{[(3R)-3-dimethylaminopropan-1-yl]carbylamine}pyridine

Range1H-NMR (CDCl3) δ (ppm): to 1.86 (1H, m), 2,17 (1H, m), and 2.27 (6H, c), by 2.73 (1H, m), 3,21 (1H, m), 3,40 (1H, m), the 3.65 (1H, m), 3,70-of 3.80 (3H, m), 6.42 per-6,55 (3H, m), 6.90 to-7,00 (2H, m), the 7.65 (1H, d, J=2.4 Hz), 8,01 (1H, d, J=5.6 Hz).

Example 246

2-{[(3S)-3-Dimethylaminopropan-1-yl]carbylamine}-4-{2-fluoro-4-[3-(2-phenylacetyl)touraid]phenoxy}pyridine

Example of getting 246-1

2-{[(3S)-3-Dimethylaminopropan-1-yl]carbylamine}-4-(2-fluoro-4-nitrophenoxy)pyridine

ESI-MS (m/z) (neg.): 388[M-H]-.

Example of getting 246-2

4-(4-Amino-2-pertenece)-2-{[(3S)-3-dimethylaminopropan-1-yl]carbylamine}pyridine

Example 247

N-(4-Forfinal)-N'-[3-fluoro-4-(2-{[(3R)-3-dimethylaminopropan-1-yl]carbylamine}pyridine-4-yloxy)phenyl]malonamic

Range1H-NMR (CDCl3) δ (ppm): 1,84 (1H, m), and 2.14 (1H, m), 2,24 (6H, c)to 2.74 (1H, m), 3,19 (1H, m)to 3.38 (1H, m), of 3.48 (2H, c), 3,61 (1H, m)to 3.67 (1H, m), of 6.66 (1H, DD, J=2,4, 5,6 Hz), 6,95-7,05 (3H, m), 7,11 (1H, m,), 7,22 (1H, m), 7,49-rate of 7.54 (2H, m), to 7.59 (1H, d, J=2.4 Hz), 7,66 (1H, DD, J=2,4, 12.0 Hz), 8,08 (1H, d, J=8,8 Hz), 8,93 (1H, Sirs), for 9.47 (1H, Sirs).

Example 248

N-(4-Forfinal)-N'-[3-fluoro-4-(2-{[(3S)-3-dimethylaminopropan-1-yl]carbylamine}pyridine-4-yloxy)phenyl]malonamic

Example 249

2-{[(3R)-3-Dimethylaminopropan-1-yl]carbylamine}-4-{2-fluoro-4-[3-(2-phenylacetyl)ureido]phenoxy}pyridine

Range1H-NMR (CDCl3) δ (ppm): to 1.86 (1H, m), 2,17 (1H, m), and 2.27 (6H, c), by 2.73 (1H, m), 3,20 (1, m), 3,40 (1H, m), the 3.65 (1H, m), of 3.73 (1H, m in), 3.75 (2H, c), is 6.54 (1H, DD, J=2,4, 5,6 Hz), 7,01 (1H, c), 7,10-7,20 (2H, m), 7.29 trend was 7.45 (5H, m), of 7.64 (1H, DD, J=2,4, 12.0 Hz), 7,66 (1H, d, J=2.4 Hz), to 7.93 (1H, Sirs), of 8.04 (1H, d, J=5.6 Hz), 10,59 (1H, c).

ESI-MS (m/z): 521[M+H]+.

Example 250

2-{[(3S)-3-Dimethylaminopropan-1-yl]carbylamine}-4-{2-fluoro-4-[3-(2-phenylacetyl)ureido]phenoxy}pyridine

Example 251

4-{2-Fluoro-4-[3-(2-phenylacetyl)touraid]phenoxy}-2-{[(2S)-2-hydroxyethylpyrrolidine-1-yl]carbylamine}pyridine

Range (1H-NMR CDCl3) δ (ppm): 1,60-1,70 (1H, m), 1,90-2,10 (3H, m), 3,40-of 3.80 (4H, m in), 3.75 (2H, c), is 4.15 (1H, m), of 6.52 (1H, m), 7,10-to 7.50 (8H, m), 7,89 (1H, m), of 8.06 (1H, m), to 8.45 (1H, Sirs), 12,45 (1H, Sirs).

ESI-MS (m/z): 524[M+H]+.

Example of getting 251-1

4-(2-Fluoro-4-nitrophenoxy)-2-{[(2S)-2-hydroxyethylpyrrolidine-1-yl]carbylamine}pyridine

Range1H-NMR (CDCl3) δ (ppm): 1.69 in (1H, m), 1,90-2,00 (2H, m)to 2.06 (1H, m), 3,40-of 3.80 (4H, m), 4,14 (1H, m), 6,62 (1H, DD, J=2,4, 5,6 Hz), 7,30 (1H, m), of 7.75 (1H, d, J=2.4 Hz), 8,08-8.16 (3H, m).

Example of getting 251-2

4-(4-Amino-2-pertenece)-2-{[(2S)-2-hydroxyethylpyrrolidine-1-yl]carbylamine}pyridine

Range1H-NMR (CDCl3) δ (ppm): of 1.66 (1H, m), 1,90-of 2.20 (3H, m), 3,40-of 3.80 (6H, m), is 4.15 (1H, m), 6,45 (1H, m), 6,47-6,53 (2H, m), to 6.95 (1H, m), 7,63 (1H, Sirs), 8,01 (1H, d, J=5.6 Hz).

Example 252

4-{2-Fluoro-4-[3-(2-phenylacetyl)touraid]phenoxy}-2-{[(2R)-2-hydroxyethylpyrrolidine-1-yl]carbylamine}pyridine

Example of getting 252-1

4-(2-Fluoro-4-nitrophenoxy)-2-{[(2R)-2-hydroxyethylpyrrolidine-1-yl]ka is Beniamino}pyridine

ESI-MS (m/z): 399[M+Na]+.

Example of getting 252-2

4-(4-Amino-2-pertenece)-2-{[(2R)-2-hydroxyethylpyrrolidine-1-yl]carbylamine}pyridine

Example 253

N-(4-{2-[(3-Dimethylimidazolidin-1-carbonyl)amino]pyridine-4-yloxy}-2-forfinal)-N'-(4-forfinal)malonamide

Range1H-NMR (CDCl3) δ (ppm): to 2.18 (6H, c), of 3.13 (1H, m), 3,55 (2H, c), 3,90 (2H, m), Android 4.04 (2H, m), 6,55 (1H, DD, J=2,4, 5,6 Hz), for 6.81 (1H, c)6,91 (2H, d, J=9.6 Hz),? 7.04 baby mortality (2H, m), 7,53 (2H, m), the 7.65 (1H, d, J=2,4 Hz), of 8.06 (1H, d, J=5.6 Hz), of 8.27 (1H, m), 8,67 (1H, c), 8,78 (1H, c).

ESI-MS (m/z): 525[M+H]+, 547[M+Na]+.

Example 254

4-{[(3S)-3-Dimethylaminopropan-1-yl]carbylamine}-6-(2-fluoro-4-{3-[2-(4-forfinal)acetyl]touraid}phenoxy)pyrimidine

Range1H-NMR (CDCl3) δ (ppm): 1,92 (1H, m), of 2.21 (1H, m), is 2.30 (6H, c), 2,78 (1H, m), 3,26 (1H, m), 3,40-to 3.52 (1H, m), 3,64-a-3.84 (2H, m), and 3.72 (2H, c), 7,10-7,40 (7H, m), of 7.70 (1H, d, J=0.8 Hz), 7,87 (1H, DD, J=2,4, 11.2 Hz), a 8.34 (1H, d, J=0.8 Hz), 8,44 (1H, Sirs), KZT 12.39 (1H, Sirs).

ESI-MS (m/z) (neg.): 554[M-H]-.

Example of getting 254-1

4-{[(3S)-3-Dimethylaminopropan-1-yl]carbylamine}-6-(2-fluoro-4-nitrophenoxy)pyrimidine

Range1H-NMR (CDCl3) δ (ppm): 1,92 (1H, m), of 2.21 (1H, m), is 2.30 (6H, c)2,80 (1H, m), or 3.28 (1H, m), 3,47 (1H, m), 3,60-of 3.85 (2H, m), 7,19 (1H, c), 7,42 (1H, m), 7,80 (1H, d, J=1.2 Hz), 8,08-of 8.15 (2H, m), with 8.33 (1H, d, J=1.2 Hz).

Example of getting 254-2

4-(4-Amino-2-pertenece)-6-{[(3S)-3-dimethylaminopropan-1-yl]carbylamine}pyrimidine

Range1H-NMR (CDCl3) δ (ppm): 1,89 (1H, m), of 2.20 (1H, m), is 2.30 (6H, c)2,77 (1H, m)of 3.25 (1H, m), 3,44 (1H, m), 3,60-are 3.90 (4H, m), 6.30-in-6,55 (2H, m), 6,97 (1H, m), 7,12 (1H, c), to 7.61 (1H, c), of 8.37 (1H, c).

Example 255

3-(4-{2-Fluoro-4-[3-(2-phenylacetyl)touraid]phenoxy}pyridine-2-yl)-1-[(2R)-2-hydroxy-3-(pyrrolidin-1-yl)propyl]-1-metalmachine

Range1H-NMR (CDCl3) δ (ppm): 1,76-of 1.84 (4H, m), is 2.37 (1H, DD, J=4,0, 12.0 Hz), 2,46-of 2.56 (2H, m), 2,64-to 2.74 (3H, m)of 3.00 (3H, c), 3,32-3,44 (2H, m), 3,74 (2H, c), 3,93 (1H, m), of 6.49 (1H, DD, J=2,4, 5,6 Hz), 7,16 (1H, m), 7,30-7,46 (7H, m), EUR 7.57 (1H, d, J=2.4 Hz), 7,88 (1H, DD, J=2,4, 12.0 Hz), 8,08 (1H, d, J=5.6 Hz), 12,42 (1H, c).

ESI-MS (m/z): 581[M+H]+.

Example of getting 255-1

N-Benzyl-N-methyl-N-(2S)-oxiranylmethyl

Sodium hydride (60%, 88 mg) is suspended in tetrahydrofuran (5 ml) at room temperature in a nitrogen atmosphere and with stirring is added dropwise N-methylbenzylamine (0,284 ml). After 1 hour, add (2R)-glycidylether (457 mg) and the reaction mixture was stirred over night at room temperature, then at 50°C for 7.5 hours. The reaction mixture is distributed between ethyl acetate and water. The organic layer was washed with saturated saline and dried over anhydrous sodium sulfate. The solvent is evaporated and get the remainder, which is purified column chromatography on silica gel (eluent: ethyl acetate), obtaining mentioned in the title compound (225 mg, 64%) as a colourless oil.

Range1H-NMR (CDCl3) δ (ppm): of 2.33 (3H, c), a 2.36 (1H, m), 2.49 USD (1H, m), 2,72-and 2.79 (2H, m), of 3.12 (1H, m), 3,52 (1H, d, J=13,2 Hz, to 3.67 (1H, d, J=13,2 Hz), 7,20-7,40 (5H, m).

Example of getting 255-2

(2R)-1-(Benzylmethylamine)-3-(pyrrolidin-1-yl)-2-propanol

N-Benzyl-N-methyl-N-(2S)-oxiranylmethyl (318 mg) was dissolved in tetrahydrofuran (3.5 ml) at room temperature in a nitrogen atmosphere and with stirring, add dropwise pyrrolidine (1.5 ml). The reaction mixture was stirred over night at room temperature, then overnight at 70°C. the Reaction mixture is evaporated and get the remainder, which is purified column chromatography on silica gel (Fuji Silysia NH, eluent: ethyl acetate), obtaining mentioned in the title compound (420 mg, 95%) as a colourless oil.

Range1H-NMR (CDCl3) δ (ppm): 1,74-of 1.80 (4H, m), of 2.25 (3H, c), 2,37-to 2.65 (8H, m), 3,52 (1H, d, J=13,2 Hz), 3,63 (1H, d, J=13,2 Hz), a 3.87 (1H, m), 7,20-7,40 (5H, m).

Example of getting 255-3

(2S)-1-(Methylamino)-3-(pyrrolidin-1-yl)-2-propanol

(2R)-1-(Benzylmethylamine)-3-(pyrrolidin-1-yl)-2-propanol (420 mg) was dissolved in methanol (10 ml). Added 10% palladium hydroxide on coal (460 mg), followed by stirring in an atmosphere of hydrogen for 4.5 hours. The reaction mixture is filtered to remove the catalyst, then the catalyst was washed with methanol. The filtrate and washings are combined and concentrated under reduced pressure, obtaining a residue, which is dried under reduced pressure and get listed in the title compound (232 mg, 87%) as a demon who Vatan oil.

Range1H-NMR (CDCl3) δ (ppm): 1,75-of 1.85 (4H, m), of 2.34 (1H, m), 2,40-2,60 (3H, m), 2,46 (3H, c), 2,60-of 2.75 (4H, m), 3,82 (1H, m).

Example of getting 255-4

3-[4-(4-Amino-2-pertenece)pyridine-2-yl]-1-[(2R)-2-hydroxy-3-(pyrrolidin-1-yl)propyl]-1-metalmachine

Range1H-NMR (CDCl3) δ (ppm): 1,70-1,90 (4H, m), is 2.37 (1H, DD, J=4,0, 12.0 Hz), 2,40-2,60 (2H, m), 2,60 is 2.80 (3H, m), 3,01 (3H, c), 3,30-3,50 (2H, m), and 3.72 (2H, Sirs), 3,93 (1H, m), 6,40-6,60 (3H, m), to 6.95 (1H, m), 7,53 (1H, d, J=1.6 Hz), of 8.04 (1H, d, J=6.0 Hz).

Example 256

3-(4-{2-Fluoro-4-[3-(2-phenylacetyl)touraid]phenoxy}pyridine-2-yl)-1-[(2S)-2-hydroxy-3-(pyrrolidin-1-yl)propyl]-1-metalmachine

Example of getting 256-1

N-benzyl-N-methyl-N-(2R)-oxiranylmethyl

Specified in the title compound obtained as a colorless oil (534 mg, 60%) in nitrogen atmosphere from sodium hydride (60%, 220 mg), N-methylbenzylamine (0,710 ml) and (2S)-glycidylmethacrylate (1,14 g).

Example of getting 256-2

(2S)-1-(Benzylmethylamine)-3-(pyrrolidin-1-yl)-2-propanol

Specified in the title compound obtained as a colorless oil (718 mg, 96%) in nitrogen atmosphere from N-benzyl-N-methyl-N-(2R)-oxiranylmethyl (533 mg).

Example of getting 256-3

(2R)-1-(Methylamino)-3-(pyrrolidin-1-yl)-2-propanol

Specified in the title compound obtained as a colorless oil (418 mg, 91%) of (2S)-1-(benzylmethylamine)-3-(pyrrolidin-1-yl)-2-propanol (718 mg).

ESI-MS (m/z): 159[M+H]+.

Example of getting 256-4

3-[4-(4-Amino-2-terfenol and)pyridine-2-yl]-1-[(2S)-2-hydroxy-3-(pyrrolidin-1-yl)propyl]-1-metalmachine

ESI-MS (m/z): 404[M+H]+.

Example 257

N-(3-Fluoro-4-{2-[3-methyl-3-(1-methylpiperidin-4-yl)ureido]pyridine-4-yloxy}phenyl)-N'-phenylmalonamide

Range1H-NMR (CDCl3) δ (ppm): 1,50-1,80 (4H, m), a 2.01 (2H, m), of 2.25 (3H, c), 2,87 (3H, c), 2,90 (2H, m), 3,51 (2H, c), 4,10 (1H, m), 6,60 (1H, DD, J=2,4, 6,0 Hz), 7,08-7,20 (2H, m), 7,20-7,30 (2H, m), 7,34 (2H, m), 7,56 (2H, m), a 7.62 (1H, d, J=2.4 Hz), 7,71 (1H, DD, J=2,4, 12.0 Hz), 8,07 (1H, d, J=6.0 Hz), the rate of 8.75 (1H, Sirs), 9,48 (1H, Sirs).

ESI-MS (m/z): 535[M+H]+.

Example 258

4-{2-Fluoro-4-[3-(2-phenylacetyl)touraid]phenoxy}-2-{[4-(morpholine-4-yl)piperidine-1-yl]carbylamine}pyridine

Range1H-NMR (CDCl3) δ (ppm): 1,40-of 1.55 (2H, m), 1.85 to 1,95 (2H, m), of 2.38 (1H, m), 2,50-2,60 (4H, m), 2,85-2,95 (2H, m), 3,70-to 3.73 (4H, m), 3,74 (2H, c), 4,05-to 4.15 (2H, m), is 6.54 (1H, DD, J=2,4, 5,6 Hz), 7,16 (1H, m), 7,30-was 7.45 (7H, m), to 7.61 (1H, c), 7,89 (1H, DD, J=2,4, 11.2 Hz), with 8.05 (1H, d, J=5.6 Hz), 8,71 (1H, Sirs), 12,46 (1H, c).

ESI-MS (m/z) (neg.): 591[M-H]-.

Example of getting 258-1

4-(2-Fluoro-4-nitrophenoxy)-2-{[4-(morpholine-4-yl)piperidine-1-yl]carbylamine}pyridine

Range1H-NMR (CDCl3) δ (ppm): 1,43-to 1.60 (2H, m), 1.85 to 1,95 (2H, m), 2,39 (1H, m), 2,50-2,60 (4H, m), 2,85-of 2.97 (2H, m), 3,65-of 3.80 (4H, m), 4,00-to 4.15 (2H, m), only 6.64 (1H, DD, J=2,4, 5,6 Hz), 7,20 was 7.36 (2H, m), of 7.69 (1H, d, J=2.0 Hz), 8,06-8,18 (3H, m).

Example of getting 258-2

4-(4-Amino-2-pertenece)-2-{[4-(morpholine-4-yl)piperidine-1-yl]carbylamine}pyridine

Range1H-NMR (CDCl3) δ (ppm): 1,45-to 1.60 (2H, m), 1,80-of 1.95 (2H, m), 2,39 (1H, m), 2,50-2,60 (4H, m), 2,85-2,95 (2H, m), 3,65-of 3.80 (6H, m), 4,05-to 4.15 (2H, m), 6,46 (1H, m), 6.48 in-6,56 (2H, m), of 6.96 (1H, m), 7,21 (1H, Sirs),7,58 (1H, d, J=1.6 Hz), 8,01 (1H, d, J=5.6 Hz).

Example 259

4-{2-Fluoro-4-[3-(2-phenylacetyl)ureido]phenoxy}-2-{[4-(morpholine-4-yl)piperidine-1-yl]carbylamine}pyridine

Range1H-NMR (CDCl3) δ (ppm): 1,30-1,45 (2H, m)of 1.65 and 1.80 (2H, m), 2,31 (1H, m), 2.40 a-2,50 (4H, m), 2.70 height is 2.80 (2H, m), 3,50-3,60 (4H, m), 3,74 (2H, c), 4,05-to 4.15 (2H, m), to 6.58 (1H, m), 7,20 is 7.50 (8H, m), 7,76 (1H, d, J=12.0 Hz), 8,11 (1H, d, J=5.6 Hz), of 9.21 (1H, c), 10,61 (1H, c)11,05 (1H, Sirs).

ESI-MS (m/z): 577[M+H]+.

Example 260

N-(4-Forfinal)-N'-(2-fluoro-4-{2-[(3-pyrrolidin-1-ilisation-1-carbonyl)amino]pyridine-4-yloxy}phenyl)malonamide

Range1H-NMR (CDCl3) δ (ppm): to 1.83 (4H, m)of 2.50 (4H, m)to 3.35 (1H, m), 3,55 (2H, c), of 3.96 (2H, m), 4,10 (2H, m), 6,55 (1H, DD, J=2,4, 5.8 Hz), for 6.81 (1H, c)6,91 (2H, m),? 7.04 baby mortality (2H, m), 7,53 (2H, m), the 7.65 (1H, d, J=2,4 Hz), with 8.05 (1H, d, J=5.8 Hz), compared to 8.26 (1H, m), 8,72 (1H, Sirs), 8,81 (1H, Sirs).

ESI-MS: 551[M+H]+, 573[M+Na]+.

Example 261

3-(Pyrrolidin-1-yl)azetidin-1-carboxylic acid {4-[2-fluoro-4-(3-phenylacetylamino)phenoxy]pyridine-2-yl}amide

Range1H-NMR (CDCl3) δ (ppm): to 1.83 (4H, m), of 2.51 (4H, m)to 3.36 (1H, m), 3,74 (2H, c), of 3.96 (2H, m), 4,08 (2H, m), 6,55 (1H, DD, J=2.0 a, 6,0 Hz), 6,83 (1H, c), 7,17 (1H, m), 7,30-7,46 (5H, m), 7,66 (1H, d, J=2.0 Hz), 7,89 (1H, DD, J=2,8, and 11.8 Hz), of 8.04 (1H, d, J=6.0 Hz), 8,59 (1H, c), to 12.44 (1H, c).

ESI-MS: 549[M+H]+.

Example of getting 261-1

3-(Pyrrolidin-1-yl)azetidin-1-carboxylic acid [4-(2-fluoro-4-nitrophenoxy)pyridine-2-yl]amide

Range1H-NMR (CD3OD) δ (ppm): of 1.84 (4H, m), of 2.56 (4H, m)to 3.36 (1H, m), 3,93 (2H, m), 4,13 (2H, m), of 6.71 (1H, DD, J=2,4, 5,6 Hz), 7,49 (1H, DD, J8,0, 8,8 Hz), EUR 7.57 (1H, d, J=2.4 Hz), 8,15-8,19 (2H, m), of 8.25 (1H, DD, J=2,8, 10,2 Hz).

Example of getting 261-2

3-(Pyrrolidin-1-yl)azetidin-1-carboxylic acid [4-(4-amino-2-pertenece)pyridine-2-yl]amide

Range1H-NMR (CDCl3) δ (ppm): to 1.83 (4H, m)of 2.50 (4H, m)to 3.36 (1H, m), of 3.73 (2H, c), of 3.96 (2H, m), 4,07 (2H, m), 6,44 (1H, m), of 6.49 (1H, DD, J=2,8, and 11.6 Hz), 6,53 (1H, DD, J=2,4, 6,0 Hz), to 6.75 (1H, Sirs), to 6.95 (1H, m), to 7.61 (1H, d, J=2.4 Hz), 8,00 (1H, d, J=6.0 Hz).

Example 262

N-(2-Fluoro-4-{2-[(3-hydroxyazetidine-1-carbonyl)amino]pyridine-4-yloxy}phenyl)-N'-(4-forfinal)malonamide

Range1H-NMR (CDCl3) δ (ppm): of 3.60 (2H, c), 3,91-of 3.94 (2H, m), 4,24 (2H, m), 4,60 (1H, m), 5,09 (1H, m), of 6.52 (1H, d, J=5.6 Hz), 6.89 in (2H, m), 7,01 (2H, m), 7,19 (1H, c), to 7.59 (2H, DD, J=4,0, a 7.6 Hz), to 7.67 (1H, c), with 8.05 (1H, d, J=5.6 Hz), 8,23 (1H, m), to 9.91 (1H, c), becomes 9.97 (1H, c).

ESI-MS (m/z): 498[M+H]+, 520[M+Na]+.

Example 263

3-[4-(2-Fluoro-4-{3-[2-(2-forfinal)acetyl]touraid}phenoxy)pyridine-2-yl]-1-methyl-1-(1-methylpiperidin-4-yl)urea

Range1H-NMR (CDCl3) δ (ppm): 1,40-of 1.88 (4H, m), of 2.08 (2H, m), 2,28 (3H, c), is 2.88 (3H, c), of 2.92 (2H, m), of 3.77 (2H, c), 4,17 (1H, m), is 6.54 (1H, m), 7,10-7,26 (4H, m), 7,27-7,47 (3H, m), 7,69 (1H, m), of 7.90 (1H, m), 8,06 (1H, d, J=5.6 Hz), 8,65 (1H, Sirs), 12,37 (1H, Sirs).

ESI-MS (m/z): 569[M+H]+.

Example 264

3-[4-(2-Fluoro-4-{3-[2-(4-methoxyphenyl)acetyl]touraid}phenoxy)pyridine-2-yl]-1-methyl-1-(1-methylpiperidin-4-yl)urea

Range1H-NMR (CDCl3) δ (ppm): 1,57 is 1.70 (2H, m)of 1.76 (2H, m), of 2.08 (2H, m)to 2.29 (3H, c), is 2.88 (3H, c), of 2.92 (2H, m), of 3.69 (2H, c), of 3.84 (3H, c), 4,17 (1H, m), is 6.54 (1H, DD, J=2,8, 5.6 Hz), of 6.96 (2H, DD, J=,8, 8,8 Hz), 7,10-7,31 (4H, m), 7,35 (1H, m), 7,69 (1H, Sirs), 7,89 (1H, DD, J=2,8, and 11.6 Hz), of 8.06 (1H, m), 8,44 (1H, Sirs), 12,46 (1H, Sirs).

ESI-MS (m/z): 581[M+H]+.

Example 265

3-[4-(2-Fluoro-4-{3-[2-(2-methoxyphenyl)acetyl]touraid}phenoxy)pyridine-2-yl]-1-methyl-1-(1-methylpiperidin-4-yl)urea

Range1H-NMR (CDCl3) δ (ppm): of 1.66 (2H, m), 1.77 in (2H, m), of 2.08 (2H, m)to 2.29 (3H, c), is 2.88 (3H, c), of 2.92 (2H, m), and 3.72 (2H, c)to 4.01 (3H, c), 4,17 (1H, m), 6,53 (1H, DD, J=2,4, 5,6 Hz), 7,01 (3H, m), 7,13-7,20 (2H, m,), 7,31-7,40 (2H, m), of 7.69 (1H, d, J=2.4 Hz), 7,89 (1H, DD, J=2,4, 12.0 Hz), with 8.05 (1H, Sirs), 9,41 (1H, Sirs), 12,36 (1H, Sirs).

ESI-MS (m/z): 581[M+H]+.

Example 266

3-[4-(2-Fluoro-4-{3-[2-(3-forfinal)acetyl]touraid}phenoxy)pyridine-2-yl]-1-methyl-1-(1-methylpiperidin-4-yl)urea

Range1H-NMR (CDCl3) δ (ppm): 1,50-1,70 (2H, m), 1.77 in (2H, m)2,07 (2H, m), 2,28 (3H, c), is 2.88 (3H, c), of 2.92 (2H, m), of 3.73 (2H, c), of 4.16 (1H, m), 6,55 (1H, m), 7,00-7,13 (3H, m), 7,30 (2H, m), 7,32-7,46 (2H, m), 7.68 per (1H, m), 7,88 (1H, m), of 8.06 (1H, m), at 8.60 (1H, Sirs), 12,38 (1H, Sirs).

ESI-MS (m/z): 569[M+H]+.

Example 267

4-(2-Fluoro-4-{3-[2-(4-forfinal)acetyl]touraid}phenoxy)-6-{[(3S)-3-(pyrrolidin-1-yl)pyrrolidin-1-yl]carbylamine}pyrimidine

Range1H-NMR (CDCl3) δ (ppm): of 1.78-1.90 (4H, m), 1,99 (1H, m), 2,17 (1H, m), 2,50-2,63 (4H, m), and 2.83 (1H, m)to 3.34 (1H, m), 3,47 (1H, m), 3,62-of 3.78 (2H, m), 3,71 (2H, c), 7,10-7,40 (7H, m), of 7.70 (1H, d, J=0.8 Hz), 7,86 (1H, DD, J=2,4, 11.2 Hz), with 8.33 (1H, d, J=0.8 Hz), of 8.47 (1H, Sirs), 12,38 (1H, Sirs).

Example of getting 267-1

4-(2-Fluoro-4-nitrophenoxy)-6-{[(3S)-3-(pyrrolidin-1-yl)pyrrolidin-1-yl]carbylamine}pyrimidine

When ECTR 1H-NMR (CDCl3) δ (ppm): 1,80-1,85 (4H, m), a 2.01 (1H, m), 2,19 (1H, m), 2,50-to 2.65 (4H, m), 2,85 (1H, m), 3,37 (1H, m), 3,47 (1H, m), 3,71 (1H, m), 6,92 (1H, m), 7,42 (1H, DD, J=7,6, 8,8 Hz), 8,02 (1H, c), 8,08-8,15 (2H, m), with 8.33 (1H, c).

Example of getting 267-2

4-(4-Amino-2-pertenece)-6-{[(3S)-3-(pyrrolidin-1-yl)pyrrolidin-1-yl]carbylamine}pyrimidine

ESI-MS (m/z): 387[M+H]+.

Example 268

3-[6-(2-Fluoro-4-{3-[2-(4-forfinal)acetyl]touraid}phenoxy)pyrimidine-4-yl]-1-methyl-1-[(3R)-1-methylpyrrolidine-3-yl]urea

Example of getting 268-1

3-[6-(2-Fluoro-4-nitrophenoxy)pyrimidine-4-yl]-1-methyl-1-[(3R)-1-methylpyrrolidine-3-yl]urea

Example of getting 268-2

3-[6-(4-Amino-2-pertenece)pyrimidine-4-yl]-1-methyl-1-[(3R)-1-methylpyrrolidine-3-yl]urea

Example 269

3-[4-(2-Fluoro-4-{3-[2-(3-methoxyphenyl)acetyl]touraid}phenoxy)pyridine-2-yl]-1-methyl-1-(1-methylpiperidin-4-yl)urea

Range1H-NMR (CDCl3) δ (ppm): 1,50-1,72 (2H, m)to 1.79 (2H, m), 2.00 in of 2.16 (2H, m), is 2.30 (3H, c), 2,82-of 3.00 (5H, m), and 3.72 (2H, c), 3,85 (3H, c), 4,17 (1H, m), 6,55 (1H, m), 6.75 in-7,88 (3H, m), 7,05-7,42 (4H, m), 7,69 (1H, m), of 7.90 (1H, DD, J=2,4, and 11.6 Hz), 8,07 (1H, d, J=6.0 Hz), 8,55 (1H, m), to 12.44 (1H, Sirs).

ESI-MS (m/z): 581[M+H]+.

Example 270

3-(4-{2-Fluoro-4-[3-(2-o-tolylacetic)touraid]phenoxy}pyridine-2-yl)-1-methyl-1-(1-methylpiperidin-4-yl)urea

Range1H-NMR (CDCl3) δ (ppm): 1,50-1,72 (2H, m), 1.77 in (2H, m), of 2.08 (2H, m)to 2.29 (3H, c), a 2.36 (3H, c), 2,80 are 2.98 (5H, m), of 3.77 (2H, c), 4,17 (1H, m), is 6.54 (1H, DD, J=2,4, 6,0 Hz), 7,02-7,40 (7H, m), of 7.69 (1H, d, J=the 2.4 Hz), 7,80 (1H, DD, J=2,4, 12.0 Hz), of 8.06 (1H, d, J=6,0 is C), 8,39 (1H, m), 12,47 (1H, Sirs).

ESI-MS (m/z): 565[M+H]+.

Example 271

3-(4-{2-Fluoro-4-[3-(2-m-tolylacetic)touraid]phenoxy}pyridine-2-yl)-1-methyl-1-(1-methylpiperidin-4-yl)urea

Range1H-NMR (CDCl3) δ (ppm): 1,50-1,90 (4H, m), of 2.08 (2H, m)to 2.29 (3H, c), 2,39 (3H, c), 2,80-3,10 (5H, m), 3,70 (2H, c), 4,17 (1H, m), 6,55 (1H, DD, J=2,4, 5,6 Hz), 7,00-to 7.50 (7H, m), of 7.69 (1H, d, J=2.4 Hz), 7,89 (1H, DD, J=2,4, and 11.6 Hz), of 8.06 (1H, d, J=5.6 Hz), 8,59 (1H, Sirs), 12,47 (1H, Sirs).

ESI-MS (m/z): 565[M+H]+.

Example 272

4-(2-Fluoro-4-{3-[2-(4-forfinal)acetyl]touraid}phenoxy)-6-{[(2R)-2-(pyrrolidin-1-ylmethyl)pyrrolidin-1-yl]carbylamine}pyrimidine

Range1H-NMR (CDCl3) δ (ppm): 1,63 (1H, m), 1,75-2,18 (7H, m), 2.49 USD (1H, m), 2,55-to 2.65 (2H, m), 2,70-2,95 (3H, m), 3,37 (1H, m), 3,70 (2H, c), with 3.79 (1H, m), 3,93 (1H, m), 7,00-7,40 (7H, m), 7,58 (1H, d, J=0.8 Hz), 7,83 (1H, DD, J=2,4, 11.2 Hz), of 8.28 (1H, d, J=0.8 Hz), 8,44 (1H, Sirs), 12,35 (1H, Sirs).

Example of getting 272-1

4-(4-Amino-2-pertenece)-6-{[(2R)-2-(pyrrolidin-1-ylmethyl)pyrrolidin-1-yl]carbylamine}pyrimidine

Range1H-NMR (CDCl3) δ (ppm): 1,63 (1H, m), 1.77 in-2,16 (7H, m), 2.49 USD (1H, m), 2,55-to 2.65 (2H, m), 2,70-2,95 (3H, m), 3,37 (1H, m), 3,70 (2H, Sirs), of 3.78 (1H, m), 3,93 (1H, m), 6.42 per (1H, m), of 6.45 (1H, DD, J=2,8, and 11.6 Hz), 6,97 (1H, m)to 7.50 (1H, d, J=0.8 Hz), 8,31 (1H, d, J=0.8 Hz), 12,87 (1H, Sirs).

ESI-MS (m/z): 401[M+H]+.

Example 273

3-Methylimidazolidine-1-carboxylic acid [6-(2-fluoro-4-{3-[2-(4-forfinal)acetyl]touraid}phenoxy)pyrimidine-4-yl]amide

Range1H-NMR (CDCl3) δ (ppm): 2,44 (3H, c), 2,90-to 3.02 (2H, m), 3,52-3,61 (2H, m), 3,71 (2H, ), to 4.14 (2H, c), 7,00-7,40 (7H, m), to 7.61 (1H, d, J=0.8 Hz), 7,86 (1H, DD, J=2,4, 11.2 Hz), a 8.34 (1H, d, J=0.8 Hz), to 8.57 (1H, Sirs), KZT 12.39 (1H, Sirs).

ESI-MS (m/z): 550[M+Na]+.

Example of getting 273-1

1-[6-(2-Fluoro-4-nitrophenoxy)pyrimidine-4-yl]-3-(2-methylaminomethyl)urea

Range1H-NMR (CDCl3) δ (ppm): 2.49 USD (3H, c), and 2.83 (2H, m), 3,50 (2H, m), 6,63 (1H, Sirs), 7,41 (1H, m), 8,09-of 8.15 (2H, m), of 8.37 (1H, c), cent to 8.85 (1H, Shir.).

Example of getting 273-2

1-[6-(4-Amino-2-pertenece)pyrimidine-4-yl]-3-(2-methylaminomethyl)urea

ESI-MS (m/z): 321[M+H]+.

Example of getting 273-3

3-Methylimidazolidine-1-carboxylic acid [6-(4-amino-2-pertenece)pyrimidine-4-yl]amide

To 1-[6-(4-amino-2-pertenece)pyrimidine-4-yl]-3-(2-methylaminomethyl)urea (56,8 mg)dissolved in tetrahydrofuran (5 ml), add paraformaldehyde (59 mg), followed by stirring at 80°C for 1 hour. The reaction mixture is cooled to room temperature and distributed between ethyl acetate and 2 N. aqueous sodium hydroxide solution. The organic layer is separated and washed with water and saturated saline, then dried over anhydrous sodium sulfate. The solvent is evaporated and get the remainder, which is purified column chromatography on silica gel (Fuji Silysia NH, eluent: ethyl acetate, then ethyl acetate:methanol = 95:5), receiving specified in the header of the connection (of 22.4 mg, 38%) as white powder.

Range1H-NMR (CDCl3 ) δ (ppm): 2,44 (3H, d, J=2,8 Hz), 2,98 (2H, m), of 3.57 (2H, m), of 3.73 (2H, Sirs), 4,13 (2H, d, J=2,8 Hz), 6,46 (1H, m), 6,51 (1H, DD, J=2,4, 12.0 Hz), of 6.96 (1H, m), 7,05 (1H, Sirs), to 7.61 (1H, d, J=0.8 Hz), of 8.37 (1H, d, J=0.8 Hz).

Example 274

3-(4-{2-Fluoro-4-[3-(2-p-tolylacetic)touraid]phenoxy}pyridine-2-yl)-1-methyl-1-(1-methylpiperidin-4-yl)urea

Range1H-NMR (CDCl3) δ (ppm): of 1.65 (2H, m), 1,72 (2H, m)2,07 (2H, m), 2,28 (3H, c), of 2.38 (3H, c), is 2.88 (3H, c), of 2.92 (2H, m), 3,71 (2H, c), of 4.16 (1H, m), is 6.54 (1H, DD, J=2.0 a, 6,0 Hz), 7,15-7,30 (6H, m), 7,34 (1H, m,), of 7.69 (1H, d, J=2.0 Hz), 7,89 (1H, DD, J=2,8, and 11.6 Hz), of 8.06 (1H, d, J=6.0 Hz), 8,44 (1H, Sirs), 12,45 (1H, Sirs).

ESI-MS (m/z): 565[M+H]+.

Example 275

1-(2-Dimethylaminoethyl)-3-[6-(2-fluoro-4-{3-[2-(4-forfinal)acetyl]touraid}phenoxy)pyrimidine-4-yl]-1-metalmachine

Range1H-NMR (CDCl3) δ (ppm): 2,41 (6H, c), 2,58-of 2.64 (2H, m)of 3.00 (3H, c), 3,32 is 3.40 (2H, m), 3,71 (2H, c), 7,10-7,40 (7H, m), of 7.48 (1H, c), to 7.84 (1H, DD, J=2,4, 11.2 Hz), with 8.33 (1H, c), 8,44 (1H, Sirs), 12,36 (1H, Sirs).

Example of getting 275-1

1-(2-Dimethylaminoethyl)-3-[6-(2-fluoro-4-nitrophenoxy)pyrimidine-4-yl]-1-metalmachine

Range1H-NMR (CDCl3) δ (ppm): 2,42 (6H, c), 2,60-2,63 (2H, m), 3,01 (3H, c), 3,36―3,39 (2H, m), 7,40 (1H, m), EUR 7.57 (1H, d, J=0.8 Hz), 8.07-a 8,13 (2H, m), 8,31 (1H, d, J=0.8 Hz).

Example of getting 275-2

3-[6-(4-Amino-2-pertenece)pyrimidine-4-yl]-1-(2-dimethylaminoethyl)-1-metalmachine

ESI-MS (m/z): 371[M+Na]+.

Example 276

1-[4-(2-Fluoro-4-{3-[2-(4-forfinal)acetyl]touraid}phenoxy)pyridine-2-yl]-3-(4-methylpiperazin-1-yl)urea

Range1H-NMR (CDl 3) δ (ppm): 2,32 (3H, c), a 2.36 (2H, m), 2,65 (2H, m), 2,77 (2H, m), 3,05 (2H, m), 3,71 (2H, c), 6,60 (1H, DD, J=2,4, 5,6 Hz), 7,00-7,38 (7H, m), 7,73 (1H, m), 7,88 (1H, DD, J=2,8, and 11.6 Hz), 8,11 (1H, d, J=5.6 Hz), 8,50-8,80 (2H, m), 12,40 (1H, Sirs).

ESI-MS (m/z): 556[M+H]+.

Example of getting 276-1

1-[4-(2-Fluoro-4-nitrophenoxy)pyridine-2-yl]-3-(4-methylpiperazin-1-yl)urea

Range1H-NMR (CDCl3) δ (ppm): 2,20-2,46 (5H, m), 2,50-of 3.60 (6H, m), of 6.65 (1H, DD, J=2,4, 5,6 Hz), 7,10-7,40 (2H, m), 7,81 (1H, m), 8,10 (1H, m)to 8.14 (1H, d, J=2.4 Hz), 8,21 (1H, d, J=5.6 Hz), 8,71 (1H, m).

ESI-MS (m/z): 413[M+Na]+.

Example of getting 276-2

1-[4-(4-Amino-2-pertenece)pyridine-2-yl]-3-(4-methylpiperazin-1-yl)urea

Range1H-NMR (CDCl3) δ (ppm): 2,32 (3H, c), a 2.36 (2H, m)of 2.64 (2H, m), 2,77 (2H, m), 3.04 from (2H, m in), 3.75 (2H, m), 5,44 (1H, m), 6,38-6,47 (1H, m), 6.48 in-6,60 (2H, m), 6,91-6,99 (1H, m), of 7.70 (1H, m), 8,07 (1H, d, J=12.0 Hz), at 8.60 (1H, m).

ESI-MS (m/z): 383[M+Na]+.

Example 277

3-[6-(2-Fluoro-4-{3-[2-(4-pertenece)acetyl]touraid}phenoxy)pyrimidine-4-yl]-1-methyl-1-[(1-methylisatin-3-yl)methyl]urea

Range1H-NMR (CDCl3) δ (ppm): 2,35 (3H, c), a 2.75 (1H, m), 3.04 from (3H, c), of 3.07 (2H, m), 3,39 (2H, m), 3,63 (2H, m), 3,71 (2H, c), 7,12 (2H, c), 7,21 (1H, m), 7,28 (2H, m), 7,35 (1H, c), to 7.68 (1H, c), to 7.84 (2H, m), a 8.34 (1H, c), 8,54 (1H, Sirs), 12,38 (1H, c).

ESI-MS (m/z): 556[M+H]+.

Example of getting 277-1

1-Benzhydrylamine-3-carboxylic acid of methylamide

To a solution of 1-benzhydrylamine-3-carboxylic acid (654 mg) in N,N-dimethylformamide (4.0 ml) is added triethylamine (1.0 ml), hexaflurophosphate Benz is triazole-1-yloxytris(dimethylamino)phosphonium (1.63 g) and methylamine hydrochloride (248 mg), followed by stirring at room temperature for 61,5 hours. The reaction mixture is distributed between ethyl acetate and water. The organic layer was washed with saturated saline and dried over anhydrous sodium sulfate. The organic layer is concentrated and receiving the remnant that purify column chromatography on silica gel (eluent: ethyl acetate). The fractions containing the target compound, concentrate, and get mentioned in the title compound (509 mg, 74,1%) as yellow crystals.

Range1H-NMR (CDCl3) δ (ppm): 2,85 (3H, d, J=4,8 Hz), 3,11 (1H, m)to 3.35 (2H, m), of 3.45 (2H, m), 4,51 (1H, c), 6,10 (1H, W), 7,21 (2H, m), 7,29 (4H, m), 7,39 (4H, d, J=7,6 Hz).

ESI-MS (m/z): 281[M+H]+, 303[M+Na]+.

Example of getting 277-2

tert-Butyl 3-methylcarbamoylmethyl-1-carboxylate

To a solution of crude 1-benzhydrylamine-3-carboxylic acid methylamide (2,72 g) in methanol (200 ml) was added hydrochloric acid (3.0 ml) and 20% palladium hydroxide on coal (1.0 g), followed by stirring in an atmosphere of hydrogen (0,40 MPa) for 5 hours. The catalyst removed from the reaction mixture by filtration and washed with methanol, after which the filtrate is concentrated. To the obtained residue, add hexane, allowed to stand for some time, after which the supernatant is removed with a pipette. The residue is evaporated and get the crude hydrochloride of methylamide azetidin-3-carboxylic acid (ESI-MS (m/z): 115[M+H]sup> +). To the crude product add water (20 ml), stirred in a bath containing ice water, and then to the reaction mixture are added tetrahydrofuran (10 ml), di-tert-butyl dicarbonate (2,34 g) and sodium hydrogen carbonate (2.25 g), followed by stirring at room temperature for 12.5 hours. The reaction mixture is distributed between ethyl acetate (200 ml) and saturated saline (50 ml). The organic layer is dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting residue is purified column chromatography on silica gel (eluent: heptane:ethyl acetate = 1:1 to 1:2, ethyl acetate, then ethyl acetate:methanol = 10:1 to 5:1), obtaining specified in the header connection (696 mg) as colorless crystals.

Range1H-NMR (CDCl3) δ (ppm): USD 1.43 (9H, c), 2,85 (3H, d, J=4,8 Hz)and 3.15 (1H, m), 4,01-to 4.14 (4H, m), of 5.53 (1H, Shir.).

ESI-MS (m/z): 237[M+Na]+.

Example of getting 277-3

The dihydrochloride of N-methyl-N-[(1-methylisatin-3-yl)methyl]amine

To a solution of tert-butyl 3-methylcarbamoylmethyl-1-carboxylate (696 mg) in tetrahydrofuran (10 ml) gradually add the aluminum lithium hydride (296 mg) under stirring and cooling in a bath with ice. The reaction mixture was stirred in nitrogen atmosphere at a bath with ice for 5 minutes, then at room temperature for 5 minutes. Next, the reaction mixture was stirred in the atmosphere the area of nitrogen at 65° C for 1 hour and heated under reflux for 3 hours. The reaction mixture is cooled to room temperature and add tetrahydrofuran (10 ml). The reaction mixture was stirred in a bath with ice and gradually add the aluminum lithium hydride (296 mg). The reaction mixture was stirred in nitrogen atmosphere at a bath with ice for 5 minutes, at room temperature for 5 minutes and heated under reflux for 7 hours. The reaction mixture was stirred in a bath with ice, add water (to 0.60 ml), 5 N. aqueous sodium hydroxide solution (0,60 ml) and water (1.8 ml) in that order. The reaction mixture was stirred in a bath with ice for 1 hour. The reaction mixture is filtered to remove insoluble matter, the filtrate is added 4 n hydrochloric acid in ethyl acetate (1.6 ml) and the solvent evaporated. The obtained crystals are dried, obtaining mentioned in the title compound (552 mg, 90,8%) as colorless crystals.

Range1H-NMR (CD3OD) δ (ppm): a 2.71 (3H, c)to 2.94 (3H, c), 3,30 (2H, m)to 3.38 (2H, m), 4,11 (2H, m), 4,30 (2H, m).

ESI-MS (m/z): 115[M+H]+.

Example of getting 277-4

3-[6-(2-Fluoro-4-nitrophenoxy)pyrimidine-4-yl]-1-methyl-1-[(1-methylisatin-3-yl)methyl]urea

Range1H-NMR (CDCl3) δ (ppm): was 2.34 (3H, c), of 2.72 (1H, m), 3,05 (5H, m)to 3.35 (2H, m), the 3.65 (2H, m), 7,41 (1H, m), to 7.77 (1H, c), 8,08-to 8.14 (3H, m), with 8.33 (1H, c).

ESI (m/z): 391[M+H] +.

Example 278

3-[6-(2-Fluoro-4-{3-[2-(4-forfinal)acetyl]touraid}phenoxy)pyrimidine-4-yl]-1-methyl-1-(1-methylisatin-3-yl)urea

Range1H-NMR (CDCl3) δ (ppm): 2,50 (3H, c), 2,85 (2H, m), with 2.93 (3H, c), 3,71 (3H, m), 3,93 (1H, m), 4,13 (1H, m), 7,10 (2H, m), 7,22 (1H, m), 7,26 and 7.36 (3H, m), 7,54 (1H, m), 7,52-7,87 (2H, m), 8,42 (1H, c), 8,55 (1H, Sirs), 12,38 (1H, c).

ESI-MS (m/z): 542[M+H]+.

Example of getting 278-1

tert-Butyl 3-methylaminomethyl-1-carboxylate

To a solution of 1-Boc-azetidin-3-one (240 mg) in methanol (20 ml) is added methylamine hydrochloride (1.42 g) and 10% palladium on coal (1.0 g), followed by stirring in an atmosphere of hydrogen at room temperature for 60 hours. The reaction mixture is filtered to remove the catalyst. To the filtrate again add 10% palladium on coal (1.0 g) and stirred in hydrogen atmosphere (0,40 MPa) at room temperature for 9 hours. The reaction mixture is filtered to remove the catalyst, and the filtrate concentrated under reduced pressure. To the obtained residue is added saturated aqueous solution of sodium bicarbonate, acetate and potassium carbonate, and then distribute the mixture. The aqueous layer was extracted with ethyl acetate. The combined organic layer is dried over anhydrous sodium sulfate, concentrated under reduced pressure and get the crude specified in the title compound (216 mg) in the form of oil pale yellow color.

Range1H-NMR (CDCl3) δ (ppm): the 1.44 (9H, c), of 2.38 (3H, c), a 3.50 (1H, m)to 3.64 (2H, m), 4,07 (2H, m).

Example of getting 278-2

The dihydrochloride methyl-(1-methylisatin-3-yl)amine

To a solution of the crude tert-butyl 3-methylaminomethyl-1-carboxylate (627 mg) in tetrahydrofuran (20 ml) gradually add the aluminum lithium hydride (256 mg) under stirring and cooling in a bath with ice. The reaction mixture was stirred in nitrogen atmosphere at a bath with ice for 5 minutes, at room temperature for 5 minutes and at 80°C for 5 hours. To the reaction mixture are added water (0,256 ml), 5 N. aqueous solution of sodium hydroxide (0,256 ml) and water (0,768 ml) under stirring and cooling in a bath with ice, followed by stirring in a bath with ice for 2 hours. The reaction mixture is filtered to remove insoluble substances, and to the filtrate is added 4 n hydrochloric acid in ethyl acetate (1.6 ml). The solvent is evaporated, receiving untreated specified in the title compound (395 mg) in the form of oil pale yellow color.

ESI-MS (m/z): 101[M+H]+.

Example of getting 278-3

3-[6-(2-Fluoro-4-nitrophenoxy)pyrimidine-4-yl]-1-methyl-1-(1-methylisatin-3-yl)urea

Range1H-NMR (CDCl3) δ (ppm): 2.49 USD (3H, c), 2,84 (2H, m), 2,95 (3H, c), of 3.73 (1H, m), of 3.94 (1H, m), 4,14 (1H, m), 7,41 (1H, m), of 7.96 (1H, c), 8,08-to 8.14 (3H, m), to 8.41 (1H, c).

ESI-MS (m/z): 377[M+H]+, 399[M+Na]+.

Example 279

4-{[(2R)-2-(Dimethylaminomethyl)pyrrolidin-1-yl]carbylamine}-6-(2-fluoro-4-{3-[2-(4-forfinal)acetyl]touraid}phenoxy)pyrimidine

Range1H-NMR (CDCl3) δ (ppm): 1,55-1,65 (1H, m), 1,75-1,90 (2H, m), is 2.09 (1H, m), 2,30-of 2.50 (7H, m), 2.63 in (1H, m), 3,37 (1H, m), 3,71 (2H, c), with 3.79 (1H, m), 3,93 (1H, m), 7,00-7,40 (6H, m), 7,56 (1H, c), to 7.84 (1H, m), with 8.33 (1H, c), to 8.70 (1H, Sirs), 12,38 (1H, Sirs), 13,12 (1H, Sirs).

Example of getting 279-1

4-{[(2R)-2-(Dimethylaminomethyl)pyrrolidin-1-yl]carbylamine}-6-(2-fluoro-4-nitrophenoxy)pyrimidine

Range1H-NMR (CDCl3) δ (ppm): 1,64 (1H, m), 1,80-1,90 (2H, m), and 2.14 (1H, m), 2.40 a-2,48 (7H, m), 2,65 (1H, DD, J=10,0, 13,2 Hz), 3,39 (1H, m), 3,82 (1H, m), of 3.96 (1H, m), 7,41 (1H, m), of 7.69 (1H, d, J=0.8 Hz), 8.07-a 8,13 (2H,, m), 8,32 (1H, d, J=0.8 Hz), 13,32 (1H, Sirs).

Example of getting 279-2

4-(4-Amino-2-pertenece)-6-{[(2R)-2-(dimethylaminomethyl)pyrrolidin-1-yl]carbylamine}pyrimidine

ESI-MS (m/z): 375[M+H]+.

Example 280

3-[6-(2-Fluoro-4-{3-[2-(4-forfinal)acetyl]touraid}phenoxy)pyrimidine-4-yl]-1-methyl-1-[(2R)-(1-methylpyrrolidine-2-yl)methyl]urea

Range1H-NMR (CDCl3) δ (ppm): 1,68 (1H, m), 1,76-of 1.88 (2H, m)of 1.97 (1H, m), is 2.41 (1H, m), 2.49 USD (3H, c), 2,77 (1H, m), to 3.02 (3H, c), and 3.16 of 3.28 (2H, m), 3,50 (1H, m), 3,71 (2H, c), 7,10-7,40 (7H, m), 7,49 (1H, DD, J=the 2.4, 11.2 Hz), with 8.33 (1H, c), 8,42 (1H, Sirs), 12,36 (1H, Sirs).

Example of getting 280-1

3-[6-(2-Fluoro-4-nitrophenoxy)pyrimidine-4-yl]-1-methyl-1-[(2R)-(1-methylpyrrolidine-2-yl)methyl]urea

Range1H-NMR (CDCl3) δ (ppm): 1,64-of 2.08 (4H, m), 2,38 is 2.46 (2H, m)of 2.50 (3H, c), 2,80 (1H, m), 3,03 (3H, c), of 3.25 (1H, m), of 3.53 (1H, m), 7,40 (1H, m), to 7.59 (1H, c), 8,06-to 8.14 (2H, m), 8,32 (1H, c).

Example of getting 280-2

3-[6-(4-Amino-2-pertenece)pyrimidine-4-yl]-1-methyl-1-[(2R)-(1-methylpyrrolidine-2-yl)methyl]urea

ESI-MS (m/z): 397[M+Na]+.

Example 281

3-[6-(3-Fluoro-4-{3-[2-(4-forfinal)acetyl]touraid}phenoxy)pyrimidine-4-yl]-1-methyl-1-[(3S)-1-methylpyrrolidine-3-yl]urea

Range1H-NMR (CDCl3) δ (ppm): 1,99 (1H, m)to 2.13 (1H, m), 2,32 at 2.45 (2H, m), of 2.45 (3H, c), 3,05 (1H, m), of 3.07 (3H, c), of 3.25 (1H, m), and 3.72 (2H, c), 4,10 (1H, m), 6,97? 7.04 baby mortality (2H, m), 7,09-7,14 (2H, m), 7,20-to 7.35 (3H, m), to 7.67 (1H, c), 8.34 per-8,39 (2H, m), and 8.50 (1H, Sirs), 12,30 (1H, Sirs).

Example of getting 281-1

Benzyl N-[2-fluoro-4-(6-{3-methyl-3-[(3S)-1-methylpyrrolidine-3-yl]ureido}pyrimidine-4-yloxy)phenyl]carbamate

Range (1H-NMR CDCl3) δ (ppm): 1,99 (1H, m)to 2.13 (1H, m), 2,30-to 2.40 (2H, m)2,44 (3H, c), 3,05 (1H, m), of 3.07 (3H, c), 3,24 (1H, m), 4,13 (1H, m), 5,23 (2H, c)6,86 (1H, m), 6.90 to-6,95 (2H, m), 7,20 was 7.45 (6H, m), 7,62 (1H, d, J=0.8 Hz), 8,14 (1H, m), scored 8.38 (1H, d, J=0.8 Hz).

Example 282

4-{[(3S)-3-Dimethylaminopropan-1-yl]carbylamine}-6-(3-fluoro-4-{3-[2-(4-forfinal)acetyl]touraid}phenoxy)pyrimidine

Range1H-NMR (CDCl3) δ (ppm): 1,91 (1H, m), of 2.20 (1H, m)to 2.29 (6H, c), 2,78 (1H, m), 3,26 (1H, m), of 3.45 (1H, m), 3,60-of 3.80 (4H, m), 6.90 to-7,05 (2H, m), 7,09-to 7.15 (2H, m), 7,20-7,40 (3H, m), of 7.64 (1H, d, J=0.8 Hz), at 8.36-8,42 (2H, m), and 8.50 (1H, Sirs), 12,32 (1H, Sirs).

Example of getting 282-1

Benzyl N-(4-{6-[(3S)-(3-dimethylaminopropan-1-ylcarbonyl)amino]pyrimidine-4-yloxy}-2-forfinal)carbamate

Range1H-NMR (CDCl3) δ (ppm) 1,90 (1H, m)of 2.20 (1H, m)to 2.29 (6H, c), 2,78 (1H, m)of 3.25 (1H, m), of 3.46 (1H, m), 3,60-are 3.90 (2H, m), 5,23 (2H, c), to 6.88 (1H, m), 6,92-of 6.96 (2H, m), 7,13 (1H, Sirs), 7,33 was 7.45 (5H, m), 7,60 (1H, d, J=0.8 Hz), 8,17 (1H, m), of 8.37 (1H, d, J=0.8 Hz).

Example 283

3-(6-{2-Fluoro-4-[3-(2-o-tolylacetic)touraid]phenoxy}pyrimidine-4-yl)-1-methyl-1-(1-methylpiperidin-4-yl)urea

Range1H-NMR (CDCl3) δ (ppm): 1,20-3,00 (17H, m), 3,76 (2H, m), 4,19 (1H, m), 7,18 is 7.50 (7H, m), 7,68 (1H, m), 7,87 (1H, DD, J=2,4, and 11.6 Hz), a 8.34 (2H, m), 12,45 (1H, m).

ESI-MS (m/z): 566[M+H]+.

Example 284

3-[6-(2-Fluoro-4-{3-[2-(4-forfinal)acetyl]touraid}phenoxy)pyrimidine-4-yl]-1-methyl-1-(1-methylpiperidin-4-ylmethyl)urea

Range1H-NMR (CDCl3) δ (ppm): 1,20-1,80 (5H, m)to 1.99 (2H, m), 2,20-of 2.36 (3H, m), 2,84-of 3.00 (2H, m), 3,02-3,14 (3H, m), 3,22-to 3.34 (2H, m), 3,68-of 3.80 (2H, m), 7.03 is-7,54 (7H, m), 7.68 per-7,80 (1H, m), 7,82-of 7.96 (1H, m), 8.30 to-8,43 (1H, m), 8,46-8,66 (1H, m), 12,34-12,56 (1H, m).

ESI-MS (m/z): 584[M+H]+.

Example of getting 284-1

3-[6-(4-Amino-2-pertenece)pyrimidine-4-yl]-1-methyl-1-(1-methylpiperidin-4-ylmethyl)urea

ESI-MS (m/z): 389[M+H]+.

Example 285

1-(1-Ethylpiperazin-4-yl)-3-[6-(2-fluoro-4-{3-[2-(4-forfinal)acetyl]touraid}phenoxy)pyrimidine-4-yl]-1-metalmachine

Range1H-NMR (CDCl3) δ (ppm): 1,10 (3H, t, J=7.2 Hz), to 1.70 (2H, m), of 1.78 (2H, m), is 2.05 (2H, m), 2,43 (2H, m), 2,88-2,96 (3H, m), 3,05 (2H, m), 3,68-of 3.78 (2H, m), 4,19 (1H, m), 7,02-7,16 (2H, m), 7,17-to 7.50 (5H, m), 7,60 to 7.75 (1H, m), 7,86 (1H, DD, J=2,8, and 11.6 Hz), 8,29-to 8.40 (1H, m), 8,48 (1H, m), 12,30-12,50 (1H, m).

ESI-MS (m/z): 584[M+H]+.

Example of getting 285-1

N-(1-Ethylpiperazin-4-yl)-N-me is ylamine

To 40% solution of methylamine in methanol (1.26 g) is added acetonitrile (150 ml), 1-ethyl-4-piperidone (2.0 ml) and acetic acid (0,932 ml), then add triacetoxyborohydride sodium (6,59 g) and stirred for 1 hour. After adding a saturated aqueous solution of sodium bicarbonate (20 ml), the reaction mixture was concentrated under reduced pressure. The resulting residue is suspended in methanol (20 ml) and the reaction mixture is filtered to remove solid, which was washed with methanol (20 ml). The filtrate is concentrated under reduced pressure and the resulting residue is suspended in tetrahydrofuran (50 ml). The reaction mixture is filtered to remove solid, which is washed with tetrahydrofuran (100 ml). The filtrate is concentrated under reduced pressure, obtaining mentioned in the title compound in crude form (3.33 g) in the form of oil pale yellow color.

ESI-MS (m/z): 143[M+H]+.

Example of getting 285-2

3-[6-(4-Amino-2-pertenece)pyrimidine-4-yl]-1-(1-ethylpiperazin-4-yl)-1-metalmachine

ESI-MS (m/z): 389[M+H]+.

Example 286

1-Cyclopropyl-3-[6-(2-fluoro-4-{3-[2-(4-forfinal)acetyl]touraid}phenoxy)pyrimidine-4-yl]-1-(1-methylpiperidin-4-yl)urea

Range1H-NMR (CDCl3) δ (ppm): 0,89 (1H, m), and 0.98 (2H, m)a 1.08 (2H, m), 1,02-1,90 (2H, m), 2,12 (4H, m), of 2.34 (3H, c)to 2.99 (2H, m), and 3.72 (2H, c), 4,10 (1H, m), 7,00-7,42 (6H, m), 7,71 (1H, c), 7,86 (1H, m), compared to 8.26 (1H c), at 8.36 (1H, m), 8,51 (1H,Sirs), KZT 12.39 (1H, Sirs).

ESI-MS (m/z): 596[M+H]+.

Example of getting 286-1

3-[6-(4-Amino-2-pertenece)pyrimidine-4-yl]-1-cyclopropyl-1-(1-methylpiperidin-4-yl)urea

ESI-MS (m/z): 401[M+H]+.

Example 287

1-Ethyl-3-[6-(2-fluoro-4-{3-[2-(4-forfinal)acetyl]touraid}phenoxy)pyrimidine-4-yl]-1-(1-methylpiperidin-4-yl)urea

Range1H-NMR (CDCl3) δ (ppm): 1,28 (3H, m), 1.60-to a 1.88 (4H, m), 1,98-of 2.20 (2H, m), 2,24-2,48 (3H, m), 2,95 (2H, m), 3,32 (2H, m), 3,64 is 3.76 (2H, m)to 4.16 (1H, m), 7,00-7,16 (2H, m), 7,16-7,46 (5H, m), of 7.70 (1H, m), 7,86 (1H, DD, J=2,4, 11.2 Hz), a 8.34 (1H, m), 8,46 (1H, m), 12,37 (1H, m).

ESI-MS (m/z): 606[M+Na]+.

Example 288

3-[6-(2-Fluoro-4-{3-[2-(4-forfinal)acetyl]touraid}phenoxy)pyrimidine-4-yl]-1-methyl-1-(tetrahydropyran-4-yl)urea

Range1H-NMR (CDCl3) δ (ppm): of 1.64 (2H, m), of 1.80 (2H, DDD, J=4,4, 12,0, to 12.8 Hz), to 2.94 (3H, c), 3,51 (2H, m), 3,71 (2H, c)4,06 (2H, DD, J=4,4, to 11.6 Hz), 4,47 (1H, m), 7,12 (2H, m), 7.18 in-7,40 (5H, m), 7,68 (1H, c), 7,87 (1H, DD, J=2,8, and 11.6 Hz), 8,35 (1H, m), of 8.47 (1H, Sirs), 12,38 (1H, Sirs).

ESI-MS (m/z): 579[M+Na]+.

Example of getting 288-1

3-[6-(2-Fluoro-4-nitrophenoxy)pyrimidine-4-yl]-1-methyl-1-(tetrahydropyran-4-yl)urea

Range1H-NMR (CDCl3) δ (ppm): to 1.61 (2H, m), is 1.81 (2H, m), 2,95 (3H, c), 3,52 (2H, m), 4,07 (2H, DD, J=4,8, 12.0 Hz), 4,47 (1H, m), 7,20-7,52 (2H, m), 7,78 (1H, c)to 8.12 (2H, m), a 8.34 (1H, c).

Example 289

3-[4-(3-Fluoro-4-{3-[2-(4-forfinal)acetyl]touraid}phenoxy)pyridine-2-yl]-1-methyl-1-(1-methylpiperidin-4-yl)urea

Range1H-NMR (CDCl3) δ (ppm): of 1.66 (2H, m), of 1.80 (2H, m), 210 (2H, m)of 2.30 (3H, c), 2,89 (3H, c), with 2.93 (2H, m), and 3.72 (2H, c), 4,18 (1H, m), to 6.58 (1H, DD, J=2,4, 6,0 Hz), 6,92 (2H, d, J=8,8 Hz), 7,09-7,14 (2H, m), 7.24 to to 7.32 (3H, m), 7,74 (1H, d, J=2.4 Hz), of 8.09 (1H, d, J=6.0 Hz), 8,32 (1H, m), 8,80 (1H, Sirs), 12,31 (1H, c).

ESI-MS (m/z): 569[M+H]+.

Example 290

3-[4-(3-Fluoro-4-{3-[2-(4-forfinal)acetyl]ureido}phenoxy)pyridine-2-yl]-1-methyl-1-(1-methylpiperidin-4-yl)urea

Range1H-NMR (CDCl3) δ (ppm): to 1.83 (4H, m), of 2.15 (2H, m), of 2.34 (3H, c), 2,89 (3H, c)to 2.99 (2H, m), of 3.73 (2H, c), 4,20 (1H, m), is 6.54 (1H, DD, J=2,2, 5.8 Hz), 6.87 in-6,92 (2H, m), 7,06 for 7.12 (2H, m), 7,22-7,28 (3H, m), 7,69 (1H, d, J=2.2 Hz), 8,56 (1H, d, J=5.8 Hz), 8,15 (2H, m), 10,66 (1H, c).

ESI-MS (m/z): 553[M+H]+, 575[M+Na]+.

Example 291

1-(3-Dimethylaminopropyl)-3-[4-(3-fluoro-4-{3-[2-(4-forfinal)acetyl]touraid}phenoxy)pyridine-2-yl]-1-metalmachine

1H-NMR Spectrum (CDCl3) δ (ppm): to 1.83 (2H, m), is 2.37 2.63 in (8H, m), with 2.93 (3H, c), 3,42 (3H, t, J=6.0 Hz), and 3.72 (2H, c), 6,51 (1H, DD, J=2,4, 5,6 Hz), 6.89 in (2H, m), 7,11 (2H, m), 7,29 (3H, m), the 7.65 (1H, d, J=2.4 Hz), 8,27 (1H, m), 8,71 (1H, Sirs), 12,27 (1H, Sirs).

ESI-MS (m/z): 557[M+H]+.

Example of getting 291-1

Benzyl (4-{2-[3-(3-dimethylaminopropyl)-3-methylurea]pyridine-4-yloxy}-2-forfinal)carbamate

Range1H-NMR (CDCl3) δ (ppm): 1,74 (2H, m), 2,28 (6H, c)to 2.35 (2H, t, J=6.0 Hz), is 2.88 (3H, c), 3,40 (3H, t, J=6.0 Hz), 5,23 (2H, c), to 6.43 (1H, DD, J=2,4, 6,0 Hz), 6,83-6,89 (3H, m), 7,35-7,42 (5H, m), to 7.61 (1H, d, J=2,4 Hz), with 8.05 (1H, d, J=6.0 Hz), 8,10 (1H, Sirs).

ESI-MS (m/z): 496[M+H]+, 518[M+Na]+.

Example 292

1-[4-(3-Fluoro-4-{3-[2-(4-forfinal)acetyl]ureido}phenoxy)pyridine-2-yl]-3-(1-methylpiperidin the-4-yl)urea

Range1H-NMR (DMSO-d6) δ (ppm): to 1.38 (2H, m), of 1.78 (2H, m), 2,02 (2H, m), of 2.15 (3H, c), 2,58 (2H, m), 3,47 (1H, m in), 3.75 (2H, c), 6,55 (1H, DD, J=2,4, 5.8 Hz), 7,00 (1H, d, J=2.4 Hz), 7,03 (1H, m), 7,17 (2H, m), 7,29 (1H, DD, J=2,4, and 11.6 Hz), 7,35-7,38 (2H, m), 7,86 (1H, Sirs), 8,08 (1H, d, J=5.8 Hz), 8,17 (1H, m), of 9.02 (1H, c), of 10.73 (1H, Sirs), 11,16 (1H, c).

ESI-MS (m/z): 539[M+H]+.

Example 293

1-(3-Dimethylaminopropyl)-3-[4-(3-fluoro-4-{3-[2-(4-forfinal)acetyl]ureido}phenoxy)pyridine-2-yl]-1-metalmachine

Range1H-NMR (CDCl3) δ (ppm): or 1.77 (2H, m), 2,32 (6H, Sirs), is 2.37 (2H, m), 2,89 (3H, c), 3,40 (2H, m), of 3.73 (2H, c), 6,46 (1H, DD, J=2,4, 5.8 Hz), 6,85-of 6.90 (2H, m), 7,10 (2H, m), 7,27-to 7.35 (3H, m), to 7.61 (1H, d, J=2,4 Hz), to 7.99 (1H, m), of 8.06 (1H, d, J=5.8 Hz), 8,12 (1H, m), to 10.62 (1H, c).

ESI-MS (m/z): 541[M+H]+.

Example 294

3-[6-(2-Fluoro-4-{3-[2-(4-forfinal)acetyl]touraid}phenoxy)pyrimidine-4-yl]-1-isopropyl-1-(1-methylpiperidin-4-yl)urea

Range1H-NMR (CDCl3) δ (ppm): 0,60-5,50 (21H, m), 6.90 to to 7.75 (8H, m), a 7.85 (1H, m), with 8.33 (1H, m), 8,49 (1H, m), 12,38 (1H, m).

ESI-MS (m/z): 598[M+H]+.

Example 295

N-{3-Fluoro-4-[2-(3-methyl-3-phenylurea)pyridine-4-yloxy]phenyl}-N'-(4-forfinal)malonamide

Range1H-NMR (CDCl3) δ (ppm): with 3.27 (3H, c), 3,51 (2H, c), 6,59 (1H, DD, J=2,4, 5,6 Hz), of 6.96-was 7.08 (3H, m), 7,14 (1H, m), 7,19-7,33 (3H, m), 7,34-7,42 (1H, m), 7,43-7,58 (4H, m), 7,66 (1H, d, J=2.4 Hz), 7,71 (1H, DD, J=the 2.4, 12.0 Hz), 7,98 (1H, d, J=5.6 Hz), of 8.90 (1H, Sirs), 9,40 (1H, Sirs).

ESI-MS (m/z): 554[M+Na]+.

Example of getting 295-1

3-[4-(2-Fluoro-4-nitrophenoxy)pyridine-2-yl]-1-methyl-1-phenylacetone

Range1H-I Is R (CDCl 3) δ (ppm): 3,31 (3H, c), is 6.61 (1H, DD, J=2,0, 5.6 Hz), 7,10 (1H, m), 7,25 was 7.36 (3H, m), 7,40 (1H, m), 7,49 (2H, m), 7,82 (1H, d, J=2.0 Hz), of 8.06 (1H, d, J=5.6 Hz), 8,13 (2H, m).

Example of getting 295-2

3-[4-(4-Amino-2-pertenece)pyridine-2-yl]-1-methyl-1-phenylacetone

Range1H-NMR (CDCl3) δ (ppm): 3,31 (3H, c in), 3.75 (2H, Sirs), 6.42 per-6,57 (3H, m), of 6.96 (1H, m), 7,00 (1H, m), 7,27-7,33 (2H, m), of 7.36 (1H, m), 7,47 (2H, m), of 7.70 (1H, d, J=2.4 Hz), to $ 7.91 (1H, d, J=5.6 Hz).

ESI-MS (m/z): 375[M+Na]+.

Example 296

N-[4-(2-Fluoro-4-{3-[2-(4-forfinal)acetyl]ureido}phenoxy)pyridine-2-yl]-2-(1-methylpiperidin-4-yl)ndimethylacetamide

Range1H-NMR (CDCl3) δ (ppm): 1,30-1,50 (2H, m), 1,70-1,80 (2H, m)to 1.87 (1H, m), 1,96 e 2.06 (2H, m), 2,22 of-2.32 (5H, m), 2,82 of 2.92 (2H, m), of 3.73 (2H, c), 6,59 (1H, DD, J=2,4, 5,6 Hz), 7,10-7,30 (6H, m), of 7.64 (1H, DD, J=2,0, 12.0 Hz), 7,79 (1H, m), of 7.90 (1H, m), 7,94 (1H, Sirs), of 8.09 (1H, d, J=5.6 Hz), 10,56 (1H, Sirs).

Example of getting 296-1

tert-Butyl 4-{[4-(2-fluoro-4-nitrophenoxy)pyridine-2-ylcarbonyl]methyl}piperidine-1-carboxylate

2-Amino-4-(2-fluoro-4-nitrophenoxy)pyridine (400 mg) dissolved in dimethylformamide (4.0 ml) under nitrogen atmosphere. To this solution was added 2-[1-(tert-butoxycarbonyl)piperidine-4-yl]acetic acid (487 mg), triethylamine (0,335 ml) and BOP reagent (1.06 g) at room temperature, followed by stirring at 60°C for 3 hours. The reaction mixture is distributed between ethyl acetate and water. The organic layer is separated and washed with saturated aqueous sodium hydrogen carbonate and neymann the m salt solution, then dried over anhydrous sodium sulfate. The solvent is evaporated, receiving the remnant that purify column chromatography on silica gel (eluent: ethyl acetate:heptane = 1:2 to 1:1) and get listed in the title compound (328 mg, 43%) as a powder pale yellow color.

Range1H-NMR (CDCl3) δ (ppm): 1,20-1,50 (2H, m)of 1.45 (9H, c), 1,55-1,75 (2H, m), 2,02 (1H, m), 2,28-of 2.30 (2H, m), 2,60 is 2.80 (2H, m), 4,00-4,20 (2H, m), of 6.71 (1H, DD, J=2,0, 5.6 Hz), 7,32 (1H, m), 7,88 (1H, d, J=2.0 Hz), 8,01 (1H, Sirs), 8,10-8,16 (2H, m), to 8.20 (1H, d, J=5.6 Hz).

Example of getting 296-2

tert-Butyl 4-{[4-(4-amino-2-pertenece)pyridine-2-ylcarbonyl]methyl}piperidine-1-carboxylate

ESI-MS (m/z): 467[M+Na]+.

Example of getting 296-3

tert-Butyl 4-{[4-(2-fluoro-4-{3-[2-(4-forfinal)acetyl]ureido}phenoxy)pyridine-2-ylcarbonyl]methyl}piperidine-1-carboxylate

ESI-MS (m/z): 646[M+Na]+.

Example 297

N-[4-(2-Fluoro-4-{3-[2-(4-forfinal)acetyl]touraid}phenoxy)pyridine-2-yl]-2-(morpholine-4-yl)ndimethylacetamide

Range1H-NMR (CDCl3) δ (ppm): 2,56-of 2.64 (4H, m), of 3.13 (2H, c), and 3.72 (2H, c), 3,76-3,82 (4H, m), 6,63 (1H, DD, J=2,4, 5,6 Hz), 7,10-7,40 (6H, m), 7,86 (1H, d, J=2.4 Hz), to $ 7.91 (1H, DD, J=2,4, 12.0 Hz), 8,17 (1H, d, J=5.6 Hz), 8,48 (1H, Sirs), 9,52 (1H, Sirs), 12,41 (1H, Sirs).

ESI-MS (m/z): 564[M+Na]+.

Example of getting 297-1

N-[4-(2-Fluoro-4-nitrophenoxy)pyridine-2-yl]-2-(morpholine-4-yl)ndimethylacetamide

Range1H-NMR (CDCl3) δ (ppm): 2,60-to 2.65 (4H, m), 3,14 (2H, c), 3,78-3,82 (4H, m), 6,72 (1H, DD, J=2,4, 5,6 Hz), 7,32 (1H, m), 7,92 (1H, d, J=2.4 Hz), 8,10-8,16 (2H, m), compared to 8.26 (1H, d, J=5.6 Hz), being 9.61 (1H, Sirs).

Example of getting 297-2

N-[4-(4-Amino-2-pertenece)pyridine-2-yl]-2-(morpholine-4-yl)ndimethylacetamide

ESI-MS (m/z): 369[M+Na]+.

Example 298

N-[4-(2-Fluoro-4-{3-[2-(4-forfinal)acetyl]touraid}phenoxy)pyridine-2-yl]-2-(4-methylpiperazin-1-yl)ndimethylacetamide

Range1H-NMR (CDCl3) δ (ppm): 2,32 (3H, c), 2,44-2,70 (8H, m), of 3.12 (2H, c), and 3.72 (2H, c), 6,62 (1H, DD, J=2,4, 5,6 Hz), 7,10-7,40 (6H, m), 7,87 (1H, d, J=2.4 Hz), to $ 7.91 (1H, DD, J=2,4, 12.0 Hz), 8,17 (1H, d, J=5.6 Hz), 8,48 (1H, Sirs), to 9.57 (1H, Sirs), 12,41 (1H, Sirs).

ESI-MS (m/z): 555[M+H]+.

Example of getting 298-1

N-[4-(2-Fluoro-4-nitrophenoxy)pyridine-2-yl]-2-(4-methylpiperazin-1-yl)ndimethylacetamide

Range1H-NMR (CDCl3) δ (ppm): of 2.33 (3H, c), 2,40 is 2.80 (8H, m), 3,14 (2H, c), 6,72 (1H, DD, J=2,4, 5,6 Hz), 7,32 (1H, m), to 7.93 (1H, d, J=2.4 Hz), 8,19-8,17 (2H, m), of 8.27 (1H, d, J=5.6 Hz), to 9.66 (1H, Sirs).

Example of getting 298-2

N-[4-(4-Amino-2-pertenece)pyridine-2-yl]-2-(4-methylpiperazin-1-yl)ndimethylacetamide

ESI-MS (m/z): 382[M+Na]+.

Example 299

4-Methylpiperazin-1-carboxylic acid [4-(3-fluoro-4-{3-[2-(4-forfinal)acetyl]touraid}phenoxy)pyridine-2-yl]amide

Range1H-NMR (CDCl3) δ (ppm): 2,32 (3H, c), is 2.44 (4H, m), 3,52 (4H, m), and 3.72 (2H, c), to 6.57 (1H, DD, J=2,0, 5.6 Hz), 6,92 (2H, d, J=9,2 Hz), 7,10 (2H, m), 7,28 (2H, m), 7,31 (1H, d, J=2.0 Hz), 7,69 (1H, d, J=2.0 Hz), 8,08 (1H, d, J=5.6 Hz), with 8.33 (1H, m), 8,65 (1H, Sirs), 12,29 (1H, c).

ESI-MS: 541[M+H]+, 563[M+Na]+.

Example of getting 299-1

Benzyl (2-fluoro-4-{2-[(4-methylpiperazin-1-carbonyl)amino]p is ridin-4-yloxy}phenyl)carbamate

Range1H-NMR (CDCl3) δ (ppm): 2,31 (3H, c), 2,42 (4H, m), 3,51 (4H, m), 5,23 (2H, c), of 6.52 (1H, DD, J=2,0, 5.8 Hz), 6,85-to 6.95 (3H, m), 7,34-7,44 (6H, m), 7,63 (1H, d, J=2.0 Hz), of 8.04 (1H, d, J=2.0 Hz), 8,13 (1H, Sirs).

ESI-MS: 480[M+H]+, 502[M+Na]+.

Example 300

3-[4-[2-Fluoro-4-{3-[2-(4-forfinal)acetyl]touraid}phenoxy]pyridine-2-yl]-1-methyl-1-phenylacetone

Range1H-NMR (CDCl3) δ (ppm): 3,31 (3H, c), and 3.72 (2H, c), of 6.52 (1H, DD, J=2,4, 6,0 Hz), 7,03 (1H, Sirs), 7,10-7,33 (7H, m), 7,38 (2H, m), of 7.48 (2H, m), of 7.75 (1H, d, J=2.4 Hz), to $ 7.91 (1H, DD, J=2,4, and 11.6 Hz), of 7.97 (1H, d, J=6,0 Hz), to 8.57 (1H, Sirs), 12,41 (1H, Sirs).

ESI-MS (m/z): 548[M+H]+.

Example 301

1-(1-Acetylpiperidine-4-yl)-3-[4-(2-fluoro-4-{3-[2-(4-forfinal)acetyl]touraid}phenoxy)pyridine-2-yl]-1-metalmachine

Range1H-NMR (CDCl3) δ (ppm): 1,10-1,90 (4H, m), 2,12 (3H, c)at 2.59 (1H, m), 2,87 (3H, m), and 3.16 (1H, m), and 3.72 (2H, c), with 3.89 (1H, m), 4,46 (1H, m), was 4.76 (1H, m), to 6.57 (1H, DD, J=2,4, 5,6 Hz), 7,08-7,40 (7H, m), to 7.67 (1H, d, J=2.4 Hz), to $ 7.91 (1H, DD, J=2,4, 11.2 Hz), 8,07 (1H, d, J=5.6 Hz), at 8.60 (1H, Sirs), 12,42 (1H, Sirs).

ESI-MS (m/z): 619[M+Na]+.

Example of getting 301-1

1-(1-Acetylpiperidine-4-yl)-3-[4-(2-fluoro-4-nitrophenoxy)pyridine-2-yl]-1-metalmachine

Range1H-NMR (CDCl3) δ (ppm): 1,44-to 1.82 (4H, m), 2,12 (3H, c)at 2.59 (1H, m), 2,89 (3H, c), and 3.16 (1H, m)to 3.89 (1H, m), of 4.44 (1H, m), was 4.76 (1H, m), to 6.67 (1H, DD, J=2,4, 5,6 Hz), 7,16-7,44 (2H, m), of 7.75 (1H, d, J=2,4 Hz), 8,02 compared to 8.26 (3H, m).

Example of getting 301-2

1-(1-Acetylpiperidine-4-yl)-3-[4-(4-amino-2-pertenece)pyridine-2-yl]-1-metalmachine

Range1H-NMR (CDCl3) δ ppm): 1,30-1,90 (4H, m), 2,11 (3H, c)at 2.59 (1H, m), of 2.86 (3H, m), and 3.16 (1H, m), 3,76 (2H, Sirs), the 3.89 (1H, m), 4,46 (1H, m), and 4.75 (1H, m), 6,50-6,60 (3H, m), of 6.96 (1H, m), 7.23 percent (1H, m), a 7.62 (1H, m), 8,02 (1H, d, J=5.6 Hz).

ESI-MS (m/z): 424[M+Na]+.

Example 302

3-[6-[2-Fluoro-4-{3-[2-(4-forfinal)acetyl]touraid}phenoxy]pyrimidine-4-yl]-1-(4-methoxyphenyl)-1-metalmachine

Range1H-NMR (CDCl3) δ (ppm): 3,31 (3H, c), 3,71 (2H, c), 3,85 (3H, c), of 6.99 (2H, m), 7,12 (2H, m), 7.18 in-7,40 (7H, m), 7,74 (1H, c), a 7.85 (1H, DD, J=2,4, 11.2 Hz), 8,24 (1H, c), 8,51 (1H, Sirs), 12,38 (1H, Sirs).

ESI-MS (m/z): 601[M+Na]+.

Example of getting 302-1

3-[6-(2-Fluoro-4-nitrophenoxy)pyrimidine-4-yl]-1-(4-methoxyphenyl)-1-metalmachine

Range1H-NMR (CDCl3) δ (ppm): to 3.33 (3H, c), 3,86 (3H, c), 7,01 (2H, m), 7,19 (1H, Sirs), 7,20-7,37 (2H, m), 7,41 (1H, m), to 7.84 (1H, c), 8,11 (2H, m), 8,23 (1H, c).

ESI-MS (m/z): 436[M+Na]+.

Example of getting 302-2

3-[6-(4-Amino-2-pertenece)pyrimidine-4-yl]-1-(4-methoxyphenyl)-1-metalmachine

Range1H-NMR (CDCl3) δ (ppm): 3,30 (3H, c), of 3.73 (2H, Sirs), 3,85 (3H, c), 6,48 (2H, m), 6.90 to-7,02 (3H, m), to 7.09 (1H, m), 7.18 in-7,30 (2H, m), 7,66 (1H, m), of 8.27 (1H, m).

ESI-MS (m/z): 406[M+Na]+.

Example 303

1-(4-Dimethylaminophenyl)-3-[6-(2-fluoro-4-{3-[2-(4-forfinal)acetyl]touraid}phenoxy)pyrimidine-4-yl]-1-metalmachine

Range1H-NMR (CDCl3) δ (ppm): 3,00 (6H, c), 3,29 (3H, c), 3,71 (2H, c), 6,74 (2H, d, J=8,8 Hz), 7,00-to 7.18 (4H, m), 7,19 and 7.36 (5H, m), of 7.75 (1H, m), a 7.85 (1H, DD, J=2,4, 11.2 Hz), 8,23 (1H, m), 8,54 (1H, Sirs), 12,38 (1H, Sirs).

ESI-MS (m/z): 614[M+Na]+.

Example of getting 303-1

3-[6-(2-Fluoro-4-n is tropinone)pyrimidine-4-yl]-1-(4-dimethylaminophenyl)-1-metalmachine

Range1H-NMR (CDCl3) δ (ppm): a 3.01 (6H, c), and 3.31 (3H, c), of 6.75 (2H, m), 7,14 (2H, m), 7,28 (1H, m), 7,41 (1H, m), a 7.85 (1H, c), 8,10 (2H, m), by 8.22 (1H, c).

Example of getting 303-2

3-[6-(4-Amino-2-pertenece)pyrimidine-4-yl]-1-(4-dimethylaminophenyl)-1-metalmachine

Range1H-NMR (CDCl3) δ (ppm): 3,00 (6H, c), 3,29 (3H, c), of 3.73 (2H, Sirs), of 6.45 (1H, m), 6,50 (1H, DD, J=2,8, 12.0 Hz), 6,74 (2H, m), 6,97 (1H, m), 7,13 (2H, m), 7,19 (1H, Sirs), to 7.67 (1H, m), of 8.27 (1H, m).

ESI-MS (m/z): 419[M+Na]+.

Example 304

1-(2-Cyanoethyl)-3-{4-[2-fluoro-4-(3-phenylacetylamino)phenoxy]pyridine-2-yl}-1-metalmachine

Range1H-NMR (CDCl3) δ (ppm): to 2.67 (2H, t, J=6.4 Hz), 3,20 (3H, c), 3,66 (2H, t, J=6,4 Hz in), 3.75 (2H, c), 6,56 (1H, DD, J=2,4, 5,6 Hz), 7,10-7,58 (8H, m), the 7.65 (1H, m), to $ 7.91 (1H, DD, J=2,4, 12.0 Hz), 8,08 (1H, d, J=5,6 Hz), 8,54 (1H, Sirs), 12,46 (1H, m).

ESI-MS (m/z): 507[M+H]+.

Example of getting 304-1

3-[4-(2-Fluoro-4-nitrophenoxy)pyridine-2-yl]-1-(2-cyanoethyl)-1-metalmachine

Range1H-NMR (CDCl3) δ (ppm): to 2.67 (2H, t, J=6.4 Hz), up 3.22 (3H, c), 3,66 (2H, t, J=6.4 Hz), of 6.66 (1H, DD, J=2,0, 5.6 Hz), 7,20-7,40 (2H, m), 7,72 (1H, d, J=2.0 Hz), 8.07-a 8,19 (3H, m).

Example of getting 304-2

3-[4-(4-Amino-2-pertenece)pyridine-2-yl]-1-(2-cyanoethyl)-1-metalmachine

Range1H-NMR (CDCl3) δ (ppm): to 2.67 (2H, t, J=6.4 Hz), 3,19 (3H, c), 3,66 (2H, t, J=6.4 Hz), 3,76 (2H, Sirs), 6,46 (1H, m), of 6.52 (2H, m), of 6.96 (1H, m), 7,26 (1H, m), 7,60 (1H, Sirs), 8,03 (1H, d, J=6.0 Hz).

Example 305

4-Acetylpiperidine-1-carboxylic acid {4-[2-fluoro-4-(3-phenylacetylamino)phenoxy]pyridine-2-yl}s is d

Range1H-NMR (CDCl3) δ (ppm): 2.13 in (3H, c), 3,44-the 3.65 (6H, m), of 3.69 (2H, m in), 3.75 (2H, c), 6,56 (1H, m), 7,10-to 7.50 (8H, m), to 7.61 (1H, Sirs), of 7.90 (1H, DD, J=2,4, and 11.6 Hz), of 8.06 (1H, d, J=5.6 Hz), 8,54 (1H, Sirs), 12,45 (1H, Sirs).

ESI-MS (m/z): 573[M+Na]+.

Example of getting 305-1

4-Acetylpiperidine-1-carboxylic acid [4-(4-amino-2-pertenece)pyridine-2-yl]amide

Range1H-NMR (CDCl3) δ (ppm): 2.13 in (3H, c), 3,43-of 3.60 (6H, m), 3,68 (2H, m), 3,76 (2H, Sirs), of 6.45 (1H, DD, J=2,4, 8,8 Hz), 6.48 in-6,54 (2H, m), 6,98 (1H, m), 7,34 (1H, Sirs), EUR 7.57 (1H, Sirs), 8,02 (1H, d, J=6.0 Hz).

Example 306

N-[4-(2-Fluoro-4-{3-[2-(4-forfinal)acetyl]touraid}phenoxy)pyridine-2-yl]-2-(4-hydroxypiperidine-1-yl)ndimethylacetamide

Range1H-NMR (CDCl3) δ (ppm): 1,60-1,75 (2H, m), 1,90-2,00 (2H, m), 2,35 at 2.45 (2H, m), 2,80-2,90 (2H, m), 3,11 (2H, c), and 3.72 (2H, c), of 3.78 (1H, m), 6,62 (1H, DD, J=2,4, 5,6 Hz), 7,10-7,40 (6H, m), 7,86 (1H, d, J=2.4 Hz), to $ 7.91 (1H, DD, J=2,4, 12.0 Hz), 8,17 (1H, d, J=5.6 Hz), of 8.47 (1H, Sirs), 9,62 (1H, Sirs), 12,41 (1H, Sirs).

ESI-MS (m/z): 578[M+Na]+.

Example of getting 306-1

N-[4-(2-Fluoro-4-nitrophenoxy)pyridine-2-yl]-2-(4-hydroxypiperidine-1-yl)ndimethylacetamide

Range1H-NMR (CDCl3) δ (ppm): of 1.65 and 1.80 (2H, m), 1,90-2,10 (2H, m), 2,30 at 2.45 (2H, m), 2,80-2,90 (2H, m), of 3.12 (2H, c), with 3.79 (2H, c), 6,72 (1H, DD, J=2,4, 5,6 Hz), 7,32 (1H, m), 7,92 (1H, d, J=2.4 Hz), 8,09-8,16 (2H, m), compared to 8.26 (1H, d, J=5.6 Hz), to 9.70 (1H, Sirs).

Example of getting 306-2

N-[4-(4-Amino-2-pertenece)pyridine-2-yl]-2-(4-hydroxypiperidine-1-yl)ndimethylacetamide

ESI-MS (m/z): 383[M+Na]+.

Example 307

N-[4-(2-Fluoro-4-{3-[2-(4-forfinal)acetyl]touraid}f is noxi)pyridine-2-yl]-2-(1-methylpiperidin-4-yl)ndimethylacetamide

Range1H-NMR (CDCl3) δ (ppm): 1,28-of 1.40 (2H, m), 1,70-1,80 (2H, m)to 1.86 (1H, m), 1,90-2,00 (2H, m), 2,20-of 2.30 (5H, m), 2,78-is 2.88 (2H, m), and 3.72 (2H, c), is 6.61 (1H, DD, J=2,4, 5,6 Hz), 7,10-7,40 (6H, m), 7,83 (1H, d, J=2,4 Hz), to $ 7.91 (1H, DD, J=2,4, 12.0 Hz), 7,94 (1H, Sirs), 8,11 (1H, d, J=5.6 Hz), charged 8.52 (1H, Sirs), 12,42 (1H, Sirs).

ESI-MS (m/z): 554[M+H]+.

Example of getting 307-1

tert-Butyl 4-{[4-(2-fluoro-4-{3-[2-(4-forfinal)acetyl]touraid}phenoxy)pyridine-2-ylcarbonyl]methyl}piperidine-1-carboxylate

Range1H-NMR (CDCl3) δ (ppm): 1,10-1,30 (2H, m)of 1.45 (9H, c), 1,70-1,80 (2H, m), 2,02 (1H, m), 2,25-of 2.30 (2H, m), 2,60 is 2.80 (2H, m), and 3.72 (2H, c), 4,00-4,20 (2H, m), is 6.61 (1H, DD, J=2,4, 5,6 Hz), 7,10-7,40 (6H, m), 7,82 (1H, d, J=2.4 Hz), to $ 7.91 (1H, DD, J=2,4, 12.0 Hz), 8,02 (1H, Sirs), 8,11 (1H, d, J=5.6 Hz), 8,49 (1H, Sirs), 12,42 (1H, Sirs).

Example 308

2-{[4-(2-Hydroxyethyl)piperazine-1-yl]carbylamine}-4-(2-fluoro-4-{3-[2-(phenyl)acetyl]touraid}phenoxy)pyridine

Range1H-NMR (CDCl3) δ (ppm): 2,50-2,60 (6H, m), 3,50 of 3.56 (4H, m), 3,62-3,68 (2H, m in), 3.75 (2H, c), 6,55 (1H, DD, J=2,4, 5,6 Hz), 7,16-to 7.50 (8H, m), 7,63 (1H, d, J=2.4 Hz), of 7.90 (1H, DD, J=2,4, and 11.6 Hz), with 8.05 (1H, d, J=5.6 Hz), 8,51 (1H, Sirs), to 12.44 (1H, Sirs).

ESI-MS (m/z): 575[M+Na]+.

Example of getting 308-1

2-{[4-(2-Hydroxyethyl)piperazine-1-yl]carbylamine}-4-(2-fluoro-4-nitrophenoxy)pyridine

Range1H-NMR (CDCl3) δ (ppm): 2,40-2,70 (6H, m), 3,40-of 3.60 (4H, m), 3,66 (2H, t, J=5.6 Hz), of 6.65 (1H, DD, J=2,4, 5,6 Hz), 7,26-to 7.35 (2H, m), of 7.70 (1H, d, J=2.4 Hz), 8,00-8,16 (3H, m).

Example of getting 308-2

4-(4-Amino-2-pertenece)-2-{[4-(2-hydroxyethyl)piperazine-1-yl]carbon is a melamine}pyridine

ESI-MS (m/z): 398[M+Na]+.

Example 309

2-{[4-(2-Dimethylaminoethyl)piperazine-1-yl]carbylamine}-4-(2-fluoro-4-{3-[2-(phenyl)acetyl]touraid}phenoxy)pyridine

Range1H-NMR (CDCl3) δ (ppm): and 2.26 (6H, c), 2,40-of 2.56 (8H, m), 3,48 of 3.56 (4H, m in), 3.75 (2H, c), is 6.54 (1H, DD, J=2,4, 5,6 Hz), 7,10-to 7.50 (8H, m), of 7.64 (1H, d, J=2.4 Hz), 7,89 (1H, DD, J=2,4, and 11.6 Hz), with 8.05 (1H, d, J=5.6 Hz), 8,48 (1H, Sirs), to 12.44 (1H, Sirs).

ESI-MS (m/z): 580[M+H]+.

Example of getting 309-1

2-{[4-(2-Dimethylaminoethyl)piperazine-1-yl]carbylamine}-4-(2-fluoro-4-nitrophenoxy)pyridine

Range1H-NMR (CDCl3) δ (ppm): of 2.25 (6H, c), 2,40-to 2.55 (8H, m), 3,45-3,55 (4H, m), only 6.64 (1H, DD, J=2,4, 5,6 Hz), 7,26-7,40 (2H, m), 7,71 (1H, d, J=2.4 Hz), 8,05-8,16 (3H, m).

Example of getting 309-2

4-(4-Amino-2-pertenece)-2-{[4-(2-dimethylaminoethyl)piperazine-1-yl]carbylamine}pyridine

ESI-MS (m/z): 403[M+H]+.

Example 310

N-[4-(2-Fluoro-4-{3-[2-(4-forfinal)acetyl]touraid}phenoxy)pyridine-2-yl]-2-(4-dimethylaminopyridine-1-yl)ndimethylacetamide

Range1H-NMR (CDCl3) δ (ppm): 1,50-1,70 (2H, m), 1,78 is 1.86 (2H, m), 2,10-of 2.28 (3H, m)to 2.29 (6H, c), 2,90 are 2.98 (2H, m)to 3.09 (2H, c), and 3.72 (2H, c), 6,62 (1H, DD, J=2,4, 5,6 Hz), 7,10-7,40 (6H, m), 7,86 (1H, d, J=2.4 Hz), of 7.90 (1H, DD, J=2,4, 12.0 Hz), 8,16 (1H, d, J=5.6 Hz), 8,48 (1H, m), 9,60 (1H, Sirs), 12,40 (1H, Sirs).

ESI-MS (m/z): 583[M+H]+.

Example of getting 310-1

N-[4-(2-Fluoro-4-nitrophenoxy)pyridine-2-yl]-2-(4-dimethylaminopyridine-1-yl)ndimethylacetamide

Range1H-NMR (CDCl3) δ (ppm): 1,50-1,90 (4H, m), 2,10-of 2.28 (3H, m), is 2.30 (6H, c), 2,90-of 3.00 (2H, m), 3,11 (2H, c) 6,72 (1H, DD, J=2,4, 5,6 Hz), 7,30 (1H, m), to 7.93 (1H, d, J=2.4 Hz), 8,10-to 8.14 (2H, m), compared to 8.26 (1H, d, J=5.6 Hz), to 9.70 (1H, Sirs).

Example of getting 310-2

N-[4-(4-Amino-2-pertenece)pyridine-2-yl]-2-(4-dimethylaminopyridine-1-yl)ndimethylacetamide

ESI-MS (m/z): 388[M+H]+.

Example 311

2-{[4-(Dimethylaminomethyl)piperidine-1-yl]carbylamine}-4-(2-fluoro-4-{3-[2-(phenyl)acetyl]touraid}phenoxy)pyridine

Range1H-NMR (CDCl3) δ (ppm): of 1.10-1.20 (2H, m), of 1.65 (1H, m), 1,75-of 1.85 (2H, m), 2,10-of 2.15 (2H, m), of 2.20 (6H, c), 2,80-2,95 (2H, m), 3,74 (2H, c), 4,00-4,10 (2H, m), 6,53 (1H, DD, J=2,4, 5,6 Hz), 7,17 (1H, m), 7,20-7,50 (7H, m), of 7.64 (1H, d, J=2.4 Hz), 7,89 (1H, DD, J=2,4, 12.0 Hz), with 8.05 (1H, d, J=5.6 Hz), 8,53 (1H, Sirs), to 12.44 (1H, Sirs).

ESI-MS (m/z): 565[M+H]+.

Example of getting 311-1

2-{[4-(Dimethylaminomethyl)piperidine-1-yl]carbylamine}-4-(2-fluoro-4-nitrophenoxy)pyridine

Range1H-NMR (CDCl3) δ (ppm): 1,10-1,30 (2H, m), 1.60-to 1,90 (3H, m), 2,10-of 2.20 (2H, m), of 2.21 (6H, c), 2,80-3,00 (2H, m), 4,00-4,20 (2H, m), only 6.64 (1H, DD, J=2,4, 5,6 Hz), 7,26-7,40 (2H, m), 7,72 (1H, d, J=2.4 Hz), 8,00-8,20 (3H, m).

Example of getting 311-2

4-(4-Amino-2-pertenece)-2-{[4-(dimethylaminomethyl)piperidine-1-yl]carbylamine}pyridine

ESI-MS (m/z): 388[M+H]+.

Example 312

3-[6-(2-Fluoro-4-{3-[2-(4-forfinal)acetyl]touraid}phenoxy)pyrimidine-4-yl]-1-methyl-1-[(3R)-1-methylpiperidin-3-yl]urea

Range1H-NMR (CDCl3) δ (ppm): 1,50-of 1.85 (4H, m), from 2.00 (1H, m)of 2.16 (1H, m), 2,31 (3H, c), is 2.74 (1H, m), 2,82 (1H, m), 2,96 (3H, c), and 3.72 (2H, c), 4,10 (1H, m), 7,06-7,16 (3H, m), 7,17-to 7.32 (3H, m), 7,35 (1H, m), 7,69 (1H, c), a 7.85 (1H, DD, J=2,4, 11.2 Hz), 8,33 (1, c)to 8.62 (1H, Sirs), KZT 12.39 (1H, Sirs).

ESI-MS (m/z): 592[M+Na]+.

Example of getting 312-1

3-[6-(4-Amino-2-pertenece)pyrimidine-4-yl]-1-methyl-1-[(3R)-1-methylpiperidin-3-yl]urea

Range1H-NMR (CDCl3) δ (ppm): 1,43-of 1.84 (4H, m)of 1.97 (1H, m), 2,11 (1H, m), is 2.30 (3H, c), is 2.74 (1H, m), of 2.81 (1H, DD, J=3,6, and 10.8 Hz), to 2.94 (3H, c), of 3.73 (2H, Sirs), 4,00-4,10 (1H, m), of 6.45 (1H, DD, J=2,8, and 8.4 Hz), 6,50 (1H, m), 6,97 (1H, m), 7,22-7,27 (1H, m), to 7.61 (1H, c), at 8.36 (1H, c).

Example 313

3-[6-(4-{3-[2-(4-Chlorophenyl)acetyl]touraid}-2-pertenece)pyrimidine-4-yl]-1-methyl-1-(1-methylpiperidin-4-yl)urea

Range1H-NMR (CDCl3) δ (ppm): 1.69 in (2H, m)and 1.83 (2H, m), and 2.14 (2H, m), 2,32 (3H, c), 2,85 totaling 3.04 (5H, m), 3,71 (2H, c), is 4.21 (1H, m), 7.18 in-7,31 (3H, m), of 7.36 (2H, m), 7,37-7,44 (2H, m), 7,68 (1H, m), 7,86 (1H, DD, J=2,8, and 11.6 Hz), a 8.34 (1H, m), 8,55 (1H, m), 12,36 (1H, Sirs).

ESI-MS (m/z): 586[M+H]+.

Example 314

1-(1-Acetylpiperidine-4-yl)-3-[6-(2-fluoro-4-{3-[2-(4-forfinal)acetyl]touraid}phenoxy)pyrimidine-4-yl]-1-metalmachine

Range1H-NMR (CDCl3) δ (ppm): 1.50 is by 1.68 (2H, m), 1,69-of 1.85 (2H, m)to 2.13 (3H, c), 2,62 (1H, m), 2,90 (3H, m), 3,19 (1H, m), and 3.72 (2H, c)to 3.92 (1H, m), 4,48 (1H, m), 4,79 (1H, m), 7,12 (2H, m), 7.18 in-to 7.32 (3H, m), 7,34-7,40 (2H, m), of 7.70 (1H, m), 7,87 (1H, DD, J=2,4, and 11.6 Hz), 8,35 (1H, c), at 8.60 (1H, Sirs), 12,40 (1H, Sirs).

ESI-MS (m/z): 620[M+Na]+.

Example 315

4-(2-Dimethylaminoacetyl)piperazine-1-carboxylic acid {4-[2-fluoro-4-(3-phenylacetylamino)phenoxy]pyridine-2-yl}amide

Range1H-NMR (CDCl3) δ (ppm): 2,28 (6H, c), of 3.13 (2H, c), 3,44-of 3.60 (4H, m), 3,62-3,70 (4H, m in), 3.75 (2H, c), 6,56 (1H, m), 7,00-7,52 8H, m), a 7.62 (1H, c), of 7.90 (1H, DD, J=2,4, and 11.6 Hz), of 8.06 (1H, m), 8,59 (1H, m), 12,46 (1H, Sirs).

ESI-MS (m/z): 594[M+H]+.

Example of getting 315-1

4-(2-Dimethylaminoacetyl)piperazine-1-carboxylic acid [4-(2-fluoro-4-nitrophenoxy)pyridine-2-yl]amide

Range1H-NMR (CDCl3) δ (ppm): 2,28 (6H, c), of 3.13 (2H, c)and 3.59 (4H, m), 3,68 (4H, m), of 6.65 (1H, DD, J=2,0, 5.6 Hz), 7,28-to 7.35 (1H, m), 7,38 (1H, m), of 7.70 (1H, d, J=2.0 Hz), 8,06-8,19 (3H, m).

Example 316

3-[6-(4-{3-[2-(3-Chlorophenyl)acetyl]touraid}-2-pertenece)pyrimidine-4-yl]-1-methyl-1-(1-methylpiperidin-4-yl)urea

Range1H-NMR (CDCl3) δ (ppm): 1,58-of 1.74 (2H, m), is 1.81 (2H, m), 2,11 (2H, m), is 2.30 (3H, c), 2,86-of 3.00 (5H, m), 3,88 (2H, c), 4,19 (1H, m), 7,21 (1H, m), 7,30-7,42 (5H, m), 7,49 (1H, m), 7,68 (1H, m), 7,92 (1H, DD, J=2,4, and 11.6 Hz), a 8.34 (1H, c), at 8.60 (1H, Sirs), 12,37 (1H, Sirs).

ESI-MS (m/z): 608[M+Na]+.

Example 317

3-[6-(4-{3-[2-(2-Chlorophenyl)acetyl]touraid}-2-pertenece)pyrimidine-4-yl]-1-methyl-1-(1-methylpiperidin-4-yl)urea

Range1H-NMR (CDCl3) δ (ppm): 1,10-of 2.25 (6H, m), of 2.34 (3H, Sirs), with 2.93 (3H, c)of 3.00 (2H, m), 3,71 (2H, c)to 4.23 (1H, m), 7,08-7,49 (7H, m), 7,69 (1H, m), 7,86 (1H, DD, J=2,4, 11.2 Hz), 8,35 (1H, m), 8,56 (1H, Sirs), 12,36 (1H, Sirs).

ESI-MS (m/z): 608[M+Na]+.

Example 318

4-{2-Fluoro-4-[3-(2-phenylacetyl)touraid]phenoxy}-2-({4-[(2-hydroxyethyl)methylamino]piperidine-1-yl}carbylamine)pyridine

Range1H-NMR (CDCl3) δ (ppm): 1,40-of 1.85 (4H, m), and 2.26 (3H, c), 2,55-2,70 (3H, m), 2,85 (2H, m), of 3.56 (2H, m in), 3.75 (2H, c), 4,10-4,20 (2H, m), is 6.54 (1H, DD, J=2,4, 5,6 Hz), 7,10-to 7.50 (8H, m), 7,63 (1H, d, J=2.4 Hz), of 7.90 (1H, DD, J=2,4, 2.0 Hz), with 8.05 (1H, d, J=5.6 Hz), and 8.50 (1H, Sirs), to 12.44 (1H, Sirs).

ESI-MS (m/z): 581[M+H]+.

Example of getting 318-1

4-(2-Fluoro-4-nitrophenoxy)-2-({4-[(2-hydroxyethyl)methylamino]piperidine-1-yl}carbylamine)pyridine

Range1H-NMR (CDCl3) δ (ppm): 1,40-1,60 (2H, m), 1,70-1,90 (2H, m), and 2.27 (3H, c), 2,60-2,70 (3H, m), 2,80-2,90 (2H, m), 3,55-3,59 (2H, m), 4,00-4,20 (2H, m), only 6.64 (1H, DD, J=2,4, 5,6 Hz), 7,20-7,40 (2H, m), 7,71 (1H, d, J=2,4 Hz), 8,05-8,16 (3H, m).

Example of getting 318-2

4-(4-Amino-2-pertenece)-2-({4-[(2-hydroxyethyl)methylamino]piperidine-1-yl}carbylamine)pyridine

ESI-MS (m/z): 404[M+H]+.

Example 319

4-{2-Fluoro-4-[3-(2-phenylacetyl)touraid]phenoxy}-2-({4-[(3R)-3-hydroxypyrrolidine-1-yl]piperidine-1-yl}carbylamine)pyridine

Range1H-NMR (CDCl3) δ (ppm): 1,40-2,00 (5H, m), 2,10-to 2.40 (3H, m)2,60 (1H, m), was 2.76 (1H, m), 2,90 was 3.05 (3H, m), 3,74 (2H, c), 3,90-4,10 (2H, m), 4,34 (1H, m), is 6.54 (1H, DD, J=2,4, 5,6 Hz), 7,10-to 7.50 (8H, m), a 7.62 (1H, d, J=2.4 Hz), 7,89 (1H, DD, J=2,4, 12.0 Hz), with 8.05 (1H, d, J=5.6 Hz), 8,53 (1H, Sirs), to 12.44 (1H, Sirs).

ESI-MS (m/z): 593[M+H]+.

Example of getting 319-1

2-({4-[(3R)-3-Hydroxypyrrolidine-1-yl]piperidine-1-yl}carbylamine)-4-(2-fluoro-4-nitrophenoxy)pyridine

Range1H-NMR (CDCl3) δ (ppm): 1,35-of 1.55 (2H, m), 1.70 to 1,95 (3H, m), 2,10-to 2.40 (3H, m)2,60 (1H, m), was 2.76 (1H, m), 2,90-3,10 (3H, m)to 3.99 (1H, m), 4,20 (1H, m), 4,36 (1H, m), only 6.64 (1H, DD, J=2,4, 5,6 Hz), 7,20-7,40 (2H, m), of 7.70 (1H, d, J=2.4 Hz), 8,05-8,15 (3H, m).

Example of getting 319-2

4-(4-Amino-2-pertenece)-2-({4-[(3R)-3-hydroxypyrrolidine-1-yl]piperidine-1-yl}carbylamine)the feast of the Dean

ESI-MS (m/z): 416[M+H]+.

Example 320

4-(2-Methoxyacetyl)piperazine-1-carboxylic acid {4-[2-fluoro-4-(3-phenylacetylamino)phenoxy]pyridine-2-yl}amide

Range1H-NMR (CDCl3) δ (ppm): 3,43 (3H, c), 3,44-3,62 (6H, m), 3,68 (2H, m in), 3.75 (2H, c), of 4.13 (2H, c), 6,56 (1H, m), 7,18 (1H, m), 7,22-7,52 (7H, m), to 7.61 (1H, Sirs), of 7.90 (1H, m), of 8.06 (1H, d, J=5.6 Hz), 8,55 (1H, Sirs), 12,46 (1H, Sirs).

ESI-MS (m/z): 603[M+Na]+.

Example of getting 320-1

4-(2-Methoxyacetyl)piperazine-1-carboxylic acid [4-(2-fluoro-4-nitrophenoxy)pyridine-2-yl]amide

Range1H-NMR (CDCl3) δ (ppm): 3,43 (3H, c), of 3.46 of 3.75 (8H, m), 4,13 (2H, c), of 6.66 (1H, DD, J=2,4, 5,6 Hz), 7,31 (1H, m), 7,39 (1H, Sirs), of 7.69 (1H, d, J=2.4 Hz), 8,05-8,24 (3H, m).

Example 321

4-{2-Fluoro-4-[3-(2-phenylacetyl)touraid]phenoxy}-2-{[4-(3-hydroxyazetidine-1-yl)piperidine-1-yl]carbylamine}pyridine

Range1H-NMR (CDCl3) δ (ppm): 1,20-1,40 (2H, m)of 1.65 and 1.80 (2H, m), of 2.25 (1H, m), 2,85-2,90 (2H, m), 3.00 and-3,10 (2H, m), 3,60-3,70 (2H, m), 3,74 (2H, c), 3,80-of 3.95 (2H, m), of 4.45 (1H, m), 6,53 (1H, DD, J=2,4, 5,6 Hz), 7,10-to 7.50 (8H, m), a 7.62 (1H, d, J=2.4 Hz), 7,89 (1H, DD, J=2,4, and 11.6 Hz), of 8.04 (1H, d, J=5.6 Hz), and 8.50 (1H, m), 12,43 (1H, Sirs).

ESI-MS (m/z): 579[M+H]+.

Example of getting 321-1

4-(2-Fluoro-4-nitrophenoxy)-2-{[4-(3-hydroxyazetidine-1-yl)piperidine-1-yl]carbylamine}pyridine

Range1H-NMR (CDCl3) δ (ppm): 1,20-1,40 (2H, m), 1,60-1,80 (2H, m), and 2.26 (1H, m), 2,80-3,00 (2H, m), 3.00 and is 3.15 (2H, m), 3,60-3,70 (2H, m), 3,80-are 3.90 (2H, m), 4,46 (1H, m), only 6.64 (1H, DD, J=2,4, 5,6 Hz), 7,20-7,40 (2H, m), of 7.69 (1H, d, J=2.4 Hz), 8,00-to 8.20 (3H, m).

Sample of what I 321-2

4-(4-Amino-2-pertenece)-2-{[4-(3-hydroxyazetidine-1-yl)piperidine-1-yl]carbylamine}pyridine

ESI-MS (m/z): 402[M+H]+.

Example 322

3-[6-(2-Fluoro-4-{3-[2-(4-forfinal)acetyl]touraid}phenoxy)pyrimidine-4-yl]-1-methyl-1-[(3S)-1-methylpiperidin-3-yl]urea

Range1H-NMR (CDCl3) δ (ppm): 1,47-of 1.80 (4H, m), a 2.01 (1H, m)of 2.16 (1H, m), 2,31 (3H, c), of 2.72 (1H, m), of 2.81 (1H, m), 2,96 (3H, m), 3,71 (2H, c), 4.09 to (1H, m), 7,00-7,42 (7H, m), 7,69 (1H, m), 7,86 (1H, DD, J=2,4, the 11.6 Hz), with 8.33 (1H, m), 8,49 (1H, Sirs), 12,38 (1H, Sirs).

ESI-MS (m/z): 570[M+H]+.

Example 323

3-{4-[2-Fluoro-4-(3-phenylacetylamino)phenoxy]pyridine-2-yl}-1-(2-hydroxyethyl)-1-metalmachine

Range1H-NMR (CDCl3) δ (ppm): to 3.02 (3H, c), 3,44-of 3.60 (3H, m), 3,74 (2H, c), 3,85 (2H, t, J=4,8 Hz), of 6.52 (1H, DD, J=2,4, 5,6 Hz), 7,16 (1H, m), 7,27-of 7.48 (8H, m), EUR 7.57 (1H, Sirs), 7,89 (1H, DD, J=2,4, and 11.6 Hz), with 8.05 (1H, d, J=5.6 Hz), 8,61 (1H, Sirs).

ESI-MS (m/z): 498[M+H]+.

Example of getting 323-1

3-[4-(2-Fluoro-4-nitrophenoxy)pyridine-2-yl]-1-(2-hydroxyethyl)-1-metalmachine

Range1H-NMR (CDCl3) δ (ppm): 3,03 (3H, c), the 3.35 (1H, Sirs), 3,52 (2H, t, J=4,8 Hz), a 3.87 (2H, t, J=4,8 Hz), is 6.61 (1H, DD, J=2,4, 5,6 Hz), 7,31 (1H, m), the 7.65 (1H, m), 8,05-8,16 (4H, m).

ESI-MS (m/z): 373[M+Na]+.

Example 324

3-{6-[2-Fluoro-4-(3-phenylacetylamino)phenoxy]pyrimidine-4-yl}-1-(2-methoxyethyl)-1-metalmachine

Range1H-NMR (CDCl3) δ (ppm): 3.04 from (3H, c), of 3.48 (3H, c), 3,52 (2H, t, J=4.4 Hz), 3,62 (2H, t, J=4.4 Hz), 3,74 (2H, c), 7,18-7,49 (8H, m), 7,53 (1H, c), a 7.85 (1H, DD, J=2,4, and 11.6 Hz), 8,35 (1H, m), 8,43 (1H, Sirs), 12,41 (1H, IRS).

ESI-MS (m/z): 535[M+Na]+.

Example 325

4-{2-Fluoro-4-[3-(2-phenylacetyl)touraid]phenoxy}-2-({4-[(3S)-3-hydroxypyrrolidine-1-yl]piperidine-1-yl}carbylamine)pyridine

Range1H-NMR (CDCl3) δ (ppm): 1,40-2,00 (5H, m), 2,10-to 2.40 (3H, m)2,60 (1H, m), was 2.76 (1H, m), 2,90 was 3.05 (3H, m), 3,74 (2H, c), 3,90-4,10 (2H, m), 4,34 (1H, m), is 6.54 (1H, DD, J=2,4, 5,6 Hz), 7,10-to 7.50 (8H, m), a 7.62 (1H, d, J=2.4 Hz), 7,89 (1H, DD, J=2,4, 12.0 Hz), with 8.05 (1H, d, J=5.6 Hz), 8,53 (1H, Sirs), to 12.44 (1H, Sirs).

Example of getting 325-1

2-({4-[(3S)-3-Hydroxypyrrolidine-1-yl]piperidine-1-yl}carbylamine)-4-(2-fluoro-4-nitrophenoxy)pyridine

ESI-MS (m/z): 446[M+H]+.

Example of getting 325 stop 2

4-(4-Amino-2-pertenece)-2-({4-[(3S)-3-hydroxypyrrolidine-1-yl]piperidine-1-yl}carbylamine)pyridine

ESI-MS (m/z): 416[M+H]+.

Example 326

4-{2-Fluoro-4-[3-(2-phenylacetyl)touraid]phenoxy}-2-{[4-(1-methylpiperidin-4-yl)piperazine-1-yl]carbylamine}pyridine

Range1H-NMR (CDCl3) δ (ppm): 1,50-2,00 (6H, m), 2,20-of 2.45 (4H, m), 2,50-to 2.65 (4H, m), 2,85-2,95 (2H, m), 3,45-3,55 (4H, m), 3,74 (2H, c), is 6.54 (1H, DD, J=2,4, 5,6 Hz), 7,10-to 7.50 (8H, m), 7,63 (1H, d, J=2.4 Hz), 7,89 (1H, DD, J=2,4, and 11.6 Hz), of 8.04 (1H, d, J=5.6 Hz), and 8.50 (1H, m), to 12.44 (1H, Sirs).

ESI-MS (m/z): 606[M+H]+.

Example of getting 326-1

4-(2-Fluoro-4-nitrophenoxy)-2-{[4-(1-methylpiperidin-4-yl)piperazine-1-yl]carbylamine}pyridine

Range (1H-NMR CDCl3) δ (ppm): 1.70 to 2.00 in (5H, m), 2,20-of 2.30 (1H, m), and 2.26 (3H, c), 2,55-2,60 (4H, m), 2,80-3,00 (3H, m), 3,40-of 3.60 (4H, m), only 6.64 (1H, DD, J=2,4, 5,6 Hz), 7,20-7,40 (2H, m), of 7.70 (1H, d, J=2.4 Hz), 8,08-8,16 (3H, m).

Example of getting 326-2

4-(4-Amino-2-pertenece)-2-{[4-(1-methylpiperidin-4-yl)piperazine-1-yl]carbylamine}pyridine

ESI-MS (m/z): 429[M+H]+.

Example 327

2-{[4-(2-Dimethylaminoethyl)piperazine-1-yl]carbylamine}-4-(4-{3-[2-(4-forfinal)acetyl]touraid}phenoxy)pyridine

Range1H-NMR (CDCl3) δ (ppm): of 2.25 (6H, c), 2,40-of 2.56 (8H, m), 3,48 of 3.56 (4H, m), 3,71 (2H, c), is 6.54 (1H, DD, J=2,4, 5,6 Hz), 7,10-7,40 (7H, m), 7,60 to 7.75 (3H, m), of 8.04 (1H, d, J=5.6 Hz), 8,56 (1H, Sirs), of 12.26 (1H, Sirs).

ESI-MS (m/z): 580[M+H]+.

Example of getting 327-1

4-(4-Amino-3-chlorophenoxy)-2-{[4-(2-dimethylaminoethyl)piperazine-1-yl]carbylamine}pyridine

ESI-MS (m/z): 419[M+H]+.

Example of getting 327-2

4-(4-Aminophenoxy)-2-{[4-(2-dimethylaminoethyl)piperazine-1-yl]carbylamine}pyridine

ESI-MS (m/z): 385[M+H]+.

Example 328

4-[3-(Dimethylamino)azetidin-1-yl]piperidine-1-carboxylic acid [6-(2-fluoro-4-{3-[2-(4-forfinal)acetyl]touraid}phenoxy)pyrimidine-4-yl]amide

ESI-MS (m/z): 625[M+H]+.

Example of getting 328-1

4-[3-(Dimethylamino)azetidin-1-yl]piperidine-1-carboxylic acid [6-(2-fluoro-4-nitrophenoxy)pyrimidine-4-yl]amide

Range1H-NMR (CDCl3) δ (ppm): 1,31-of 1.39 (2H, m)of 1.76 (2H, m)to 2.13 (6H, c), 2,31 (1H, m), of 2.86 (3H, m), 3,14 (2H, m), 3,50 (2H, m), 3,90 (2H, m), 7,41 (1H, m)to 7.50 (1H, m), 7,72 (1H, c), 8,11 (2H, m), 8,31 (1H, c).

ESI-MS (m/z): 460[M+H]+.

Example 329

4-(4-{3-[2-(4-Forfinal)acetyl]touraid}phenoxy)-2-{[4-(1-methylpiperidin-4-yl)piperazine-1-yl]CT is arylamino}pyridine

Range1H-NMR (CDCl3) δ (ppm): 1,50-2,05 (6H, m), 2,20-2,40 (4H, m), 2,50-to 2.65 (4H, m), 2,85-of 3.00 (2H, m), 3,40-of 3.60 (4H, m), 3,71 (2H, c), is 6.54 (1H, DD, J=2,4, 5,6 Hz), 7,10-7,40 (7H, m), 7,60 to 7.75 (3H, m), of 8.04 (1H, d, J=5,6 Hz)and 8.50 (1H, Sirs), of 12.26 (1H, Sirs).

ESI-MS (m/z): 606[M+H]+.

Example of getting 329-1

2-{[4-(1-Methylpiperidin-4-yl)piperazine-1-yl]carbylamine}-4-(4-nitrophenoxy)pyridine

Range1H-NMR (CDCl3) δ (ppm): 1.70 to a 2.00 (6H, m), 2,20-of 2.30 (1H, m), 2,28 (3H, c), 2,55-to 2.65 (4H, m), 2,80-3,00 (2H, m), 3,40-of 3.60 (4H, m), only 6.64 (1H, DD, J=2,4, 5,6 Hz), 7,15-7,40 (3H, m), of 7.75 (1H, d, J=2.4 Hz), 8,15 (1H, d, J=5.6 Hz), 8,25-8,30 (2H, m).

Example of getting 329-2

4-(4-Aminophenoxy)-2-{[4-(1-methylpiperidin-4-yl)piperazine-1-yl]carbylamine}pyridine

ESI-MS (m/z): 411[M+H]+.

Example 330

3-{4-[2-Fluoro-4-(3-phenylacetylamino)phenoxy]pyridine-2-yl}-1-methyl-1-[1-(1-methylisatin-3-yl)piperidine-4-yl]urea

Range1H-NMR (CDCl3) δ (ppm): 1,64-to 1.77 (4H, m), at 1.91 (2H, m), 2,39 (3H, c), of 2.81 (2H, m), is 2.88 (3H, c), with 2.93 (3H, m), of 3.57 (2H, m), 3,74 (2H, c), 4,17 (1H, m), 6,55 (1H, DD, J=2,4, 5,6 Hz), 7,14-to 7.50 (9H, m), to 7.67 (1H, d, J=2.4 Hz), of 7.90 (1H, DD, J=2,4, and 11.6 Hz), of 8.06 (1H, d, J=5.6 Hz), 11,46 (1H, c).

ESI-MS (m/z): 606[M+H]+, 628[M+Na]+.

Example of getting 330-1

tert-Butyl 3-(4-tert-butoxycarbonylamino-1-yl)azetidin-1-carboxylate

1-Boc-azetidin-3-ONU (1,00 g) and 4-(tert-butoxycarbonylamino)piperidine (1,17 g)dissolved in methanol (50 ml), add acetic acid (0,368 ml) and 10% palladium on coal (1.0 g) with subsequent mixing is in the atmosphere of hydrogen at room temperature for 12 hours. The reaction mixture is stirred in hydrogen atmosphere (0.4 MPa) at room temperature for 4 hours. The reaction mixture is filtered to remove the catalyst. The filtrate is concentrated under reduced pressure. The residue is distributed between ethyl acetate and saturated aqueous sodium bicarbonate. The aqueous layer was extracted with ethyl acetate. The combined organic layer was washed with saturated saline and dried over anhydrous sodium sulfate. The organic layer is concentrated. The obtained crystals are suspended in a mixture of diethyl ether-hexane, collected by filtration and washed with hexane. Then the crystals are dried in a stream of air, getting mentioned in the title compound (1,21 g) as colorless crystals.

ESI-MS (m/z): 356[M+H]+.

Example of getting 330-2

Trihydrochloride methyl-[1-(1-methylisatin-3-yl)piperidine-4-yl]amine

To a solution of tert-butyl 3-(4-tert-butoxycarbonylamino-1-yl)azetidin-1-carboxylate (675 mg) in tetrahydrofuran (25 ml) was added aluminum lithium hydride (216 mg) in a bath with ice, followed by stirring in a bath with ice for 0.5 hours. The reaction mixture was stirred at 80°C for 4 hours. The reaction mixture is cooled in a bath with ice. To the reaction mixture while stirring, water (0,216 ml), 5 N. aqueous sodium hydroxide solution (0,216 ml) and water (1.08 ml), followed by stirring in a bath with ice for 3 hours. The reaction mixture is filtered to remove insoluble substances, and to the filtrate is added 4 n hydrochloric acid in ethyl acetate (1,43 ml). This solution is concentrated and receive untreated specified in the title compound (555 mg) as a solid pale yellow color.

ESI-MS (m/z): 184[M+H]+.

Example of getting 330-3

3-[4-(2-Fluoro-4-nitrophenoxy)pyridine-2-yl]-1-methyl-1-[1-(1-methylisatin-3-yl)piperidine-4-yl]urea

ESI-MS (m/z): 459[M+H]+.

Example of getting 330-4

3-[4-(4-Amino-2-pertenece)pyridine-2-yl]-1-methyl-1-[1-(1-methylisatin-3-yl)piperidine-4-yl]urea

ESI-MS (m/z): 429[M+H]+, 451[M+Na]+.

Example 331

3-(4-{4-[3-(4-Forfinal)acetylthiourea]phenoxy}pyridine-2-yl)-1-methyl-1-[1-(1-methylisatin-3-yl)piperidine-4-yl]urea

Range1H-NMR (CDCl3) δ (ppm): 1,62-of 1.78 (4H, m), with 1.92 (2H, m)2,44 (3H, c), of 2.81 (2H, m), 2,89 (3H, c)of 3.00 (3H, m), the 3.65 (2H, m), 3,71 (2H, c), 4,18 (1H, m), 6,55 (1H, DD, J=2,4, 5.8 Hz),? 7.04 baby mortality-to 7.18 (4H, m), 7,25-7,31 (3H, m), 7,66-of 7.70 (3H, m), of 8.06 (1H, d, J=5.8 Hz), 8,64 (1H, Sirs), 12,27 (1H, c).

ESI-MS (m/z): 606[M+H]+, 628[M+Na]+.

Example of getting 331-1

1-Methyl-1-[1-(1-methylisatin-3-yl)piperidine-4-yl]-3-[4-(4-nitrophenoxy)pyridine-2-yl]urea

Range1H-NMR (CDCl3) δ (ppm): 1,64-to 1.98 (6H, m), of 2.34 (3H, c), 2,79-2,93 (8H, m), 3,51 (2H, m), 4,17 (1H, m), of 6.65 (1H, DD, J=2,0, 5.6 Hz), 7,18 (2H, d, J=9.0 Hz), 7,26 (1H, Sirs), 7,80 (1H, d, J=2.0 Hz), 8,17 (1H, d, J=5.6 Hz), of 8.27 (2H, d, J=9.0 Hz).

ESI-MS (m/z): 441[M+] +.

Example of getting 331-2

3-[4-(4-Aminophenoxy)pyridine-2-yl]-1-methyl-1-[1-(1-methylisatin-3-yl)piperidine-4-yl]urea

Range1H-NMR (CDCl3) δ (ppm): 1,64-to 1.77 (4H, m), with 1.92 (2H, m), 2,39 (3H, c), of 2.81 (2H, m), 2,95 (3H, c), 3,18 (5H, m), of 3.60 (2H, m), 4,18 (1H, m), 6.48 in (1H, DD, J=2,0, 5.6 Hz), 6,70 (2H, d, J=8,8 Hz), make 6.90 (2H, d, J=8,8 Hz), 7,30 (1H, Sirs), to 7.61 (1H, d, J=2.0 Hz), 7,98 (1H, d, J=5.6 Hz).

ESI-MS (m/z): 411[M+H]+, 433[M+Na]+.

Example 332

(3S)-3-Dimethylaminomethylene-1-carboxylic acid [6-(2-fluoro-4-{3-[2-(4-forfinal)acetyl]touraid}phenoxy)pyrimidine-4-yl]amide

Range1H-NMR (CDCl3) δ (ppm): 1,43-of 1.74 (3H, m), of 1.80 (1H, m), 1,92-of 2.08 (2H, m), 2,31 (6H, c), 2,61 (1H, m), 2,82 (1H, m), 3,14 (1H, m), 3,71 (2H, c), with 3.89 (1H, m), 4,30 (1H, m), 7,12 (2H, m), 7,21 (1H, m), 7,25-7,31 (2H, m), 7,34 (1H, m), 7,46 (1H, c), to 7.84 (1H, DD, J=2,4, and 11.6 Hz), with 8.33 (1H, c), 8,51 (1H, Sirs), 10,80 (1H, Sirs), 12,37 (1H, Sirs).

ESI-MS (m/z): 584[M+H]+.

Example of getting 332-1

(3S)-3-Dimethylaminomethylene-1-carboxylic acid [6-(4-amino-2-pertenece)pyrimidine-4-yl]amide

Range1H-NMR (CDCl3) δ (ppm): 1,44-of 1.88 (4H, m), 1,90-of 2.09 (2H, m), 2,23 to 2.35 (6H, m)2,60 (1H, m), 2,84 (1H, m), and 3.16 (1H, m), 3,71 (2H, m), a 3.87 (1H, m), 4,27 (1H, m), to 6.43 (1H, DD, J=1,2, 2,8 Hz), 6,50 (1H, DD, J=2,8, and 11.6 Hz), 6,97 (1H, m), 7,39 (1H, m), at 8.36 (1H, m), at 10.64 (1H, m).

Example 333

(3R)-3-Dimethylaminomethylene-1-carboxylic acid [6-(2-fluoro-4-{3-[2-(4-forfinal)acetyl]touraid}phenoxy)pyrimidine-4-yl]amide

Range1H-NMR (CDCl3) δ (ppm): 1,46-1,72 (3H, m), of 1.80 (1H, m), 1,94 is 2.10 (2H, m), 2,31(6H, c)2,61 (1H, m), 2,82 (1H, m)and 3.15 (1H, m), 3,71 (2H, c), with 3.89 (1H, m), 4,30 (1H, m), 7,12 (2H, m), 7,21 (1H, m), 7.24 to 7,40 (3H, m), 7,46 (1H, c), 7,86 (1H, DD, J=2,4, and 11.6 Hz), 8,32 (1H, c), 8,51 (1H, Sirs), 10,79 (1H, Sirs), 12,34 (1H, Sirs).

ESI-MS (m/z): 584[M+H]+.

Example of getting 333-1

(3R)-3-Dimethylaminomethylene-1-carboxylic acid [6-(4-amino-2-pertenece)pyrimidine-4-yl]amide

Range1H-NMR (CDCl3) δ (ppm): 1,43 is 1.86 (4H, m), 1,95-of 2.08 (2H, m), is 2.30 (6H, m)2,60 (1H, m), and 2.83 (1H, m)and 3.15 (1H, m), 3,71 (2H, m), 3,83-with 3.79 (2H, m), 4,27 (1H, m), 6,40-6,55 (2H, m), 6,97 (1H, m), 7,38 (1H, m), at 10.64 (1H, m).

Example 334

4-(2-Dimethylaminoethyl)-[1,4]diazepan-1-carboxylic acid {4-[2-fluoro-4-(3-phenylacetylamino)phenoxy]pyridine-2-yl}amide

Range1H-NMR (CDCl3) δ (ppm): of 1.93 (2H, m), 2,24 (6H, m)to 2.41 (2H, t, J=7.2 Hz), 2.63 in (2H, t, J=7.2 Hz), 2,70 (2H, m), 2,77 (2H, m), of 3.57 (2H, m), 3,62 (2H, m in), 3.75 (2H, c), 6,53 (1H, DD, J=2,4, 5,6 Hz), 7,00-7,53 (8H, m), of 7.70 (1H, m), of 7.90 (1H, DD, J=2,4, and 11.6 Hz), of 8.06 (1H, d, J=5.6 Hz), 8,53 (1H, Sirs), 12,45 (1H, Sirs).

ESI-MS (m/z): 594[M+H]+.

Example of getting 334-1

4-(2-Dimethylaminoethyl)-[1,4]diazepan-1-carboxylic acid [4-(4-amino-2-pertenece)pyridine-2-yl]amide

Range1H-NMR (CDCl3) δ (ppm): of 1.93 (2H, m), of 2.25 (6H, c)to 2.41 (2H, t, J=7.2 Hz), 2.63 in (2H, t, J=7.2 Hz), 2,69 (2H, m), 2,77 (2H, m), of 3.56 (2H, m), of 3.60 (2H, m), 3,74 (2H, Sirs), 6,44 (1H, DD, J=2,8, and 8.4 Hz), of 6.49 (1H, d, J=2,8 Hz), of 6.52 (1H, m), of 6.96 (1H, m), 7,19 (1H, m), of 7.64 (1H, m), 8,01 (1H, m).

Example 335

(3S)-3-Dimethylaminomethylene-1-carboxylic acid {4-[2-fluoro-4-(3-phenylacetylamino)phenoxy]pyridine-2-yl}s is d

Range1H-NMR (CDCl3) δ (ppm): 1.26 in (1H, m), 1,36-of 1.56 (2H, m), of 1.78 (1H, m), of 1.95 (2H, m), 2,28 (6H, c)to 2.55 (1H, m), 2,95 (1H, m), 3,23 (1H, m), 3,70 (1H, m), 3,74 (2H, c), of 4.05 (1H, m), 6.48 in (1H, DD, J=2,4, 5,6 Hz), to 7.15 (1H, m), 7,31 (3H, m), 7,42 (3H, m), 7,55 (1H, d, J=2.0 Hz), 7,87 (1H, DD, J=2,4, and 11.6 Hz), with 8.05 (1H, d, J=5.6 Hz), 8,56 (1H, Sirs), 9,72 (1H, Sirs), 12,42 (1H, Sirs).

ESI-MS (m/z): 565[M+H]+.

Example of getting 335-1

(3S)-3-Dimethylaminomethylene-1-carboxylic acid [4-(4-amino-2-pertenece)pyridine-2-yl]amide

Range1H-NMR (CDCl3) δ (ppm): 1,25-1,50 (3H, m)of 1.76 (1H, m), of 1.94 (2H, m), and 2.27 (6H, c)of 2.53 (1H, m), 2,99 (1H, m), 3,26 (1H, m), 3,50-3,82 (3H, m)to 4.01 (1H, m), 6,25-6,60 (3H, m), 6,93 (1H, m), 7,51 (1H, m), 8,01 (1H, d, J=5.6 Hz), at 9.53 (1H, Sirs).

Example 336

(3R)-3-Dimethylaminomethylene-1-carboxylic acid {4-[2-fluoro-4-(3-phenylacetylamino)phenoxy]pyridine-2-yl}amide

Range1H-NMR (CDCl3) δ (ppm): 1,27 (1H, m), 1,36 is 1.60 (2H, m), of 1.78 (1H, m), of 1.95 (2H, m), 2,28 (6H, c)to 2.55 (1H, m), 2,95 (1H, m), 3,24 (1H, m), 3,70 (1H, m), 3,74 (2H, c), of 4.05 (1H, m), 6.48 in (1H, DD, J=2,4, 5,6 Hz), to 7.15 (1H, m), 7,32 (3H, m), 7,41 (3H, m), 7,54 (1H, d, J=2.4 Hz), 7,87 (1H, DD, J=2,4, 12.0 Hz), of 8.06 (1H, d, J=5.6 Hz), 8,61 (1H, Sirs), 9,73 (1H, Sirs), 12,42 (1H, Sirs).

ESI-MS (m/z): 565[M+H]+.

Example of getting 336-1

(3R)-3-Dimethylaminomethylene-1-carboxylic acid [4-(4-amino-2-pertenece)pyridine-2-yl]amide

Range1H-NMR (CDCl3) δ (ppm): 1,28-of 2.08 (6H, m), 2,32 (6H, c), to 2.57 (1H, m), is 3.08 (1H, m), 3,37 (1H, m)and 3.59 (1H, m), and 3.72 (2H, m), 3,91 (1H, m), 6,38-to 6.58 (4H, m), to 6.95 (1H, m), 7,52 (1H, d, J=2.0 Hz), 8,01 (1H, d, J=5.6 Hz).

Example 37

4-(1-Methylisatin-3-yl)piperazine-1-carboxylic acid [4-(4-{3-[2-(4-forfinal)acetyl]touraid}phenoxy)pyridine-2-yl]amide

Range1H-NMR (CDCl3) δ (ppm): 2,33 (4H, m), is 2.40 (3H, c), 2,98 (3H, m), 3,51 (4H, m), of 3.57 (2H, m), 3,71 (2H, c), 6,55 (1H, m), 7,12 (4H, m), 7,20-7,38 (3H, m), 7,63 (1H, c), of 7.69 (2H, d, J=8,8 Hz), with 8.05 (1H, d, J=1,6 Hz), at 8.60 (1H, Sirs), 12,27 (1H, c).

ESI-MS (m/z): 578[M+H]+.

Example of getting 337-1

4-(1-Methylisatin-3-yl)piperazine-1-carboxylic acid [4-(4-nitrophenoxy)pyridine-2-yl]amide

Range1H-NMR (CDCl3) δ (ppm): 2,32-of 2.38 (7H, m), with 2.93 (3H, m), 3,52 (6H, m), of 6.65 (1H, DD, J=2,4, 5,6 Hz), 7,19 (2H, d, J=9,2 Hz), was 7.36 (1H, m), of 7.75 (1H, d, J=2.4 Hz), 8,16 (1H, d, J=5.6 Hz), of 8.28 (2H, d, J=9,2 Hz).

ESI-MS (m/z): 413[M+H]+.

Example of getting 337-2

4-(1-Methylisatin-3-yl)piperazine-1-carboxylic acid [4-(4-aminophenoxy)pyridine-2-yl]amide

ESI-MS (m/z): 383[M+H]+, 405[M+Na]+.

Example 338

4-(Azetidin-1-yl)piperidine-1-carboxylic acid [4-(4-{3-[2-(4-forfinal)acetyl]touraid}phenoxy)pyridine-2-yl]amide

Range1H-NMR (CDCl3) δ (ppm): 1,24-of 1.27 (2H, m), 1,72 (2H, m)to 2.06 (2H, m), of 2.21 (1H, m), 3.04 from (2H, m), 3,19 (4H, m), 3,71 (2H, c), 3,90 (2H, m), 6,53 (1H, DD, J=2.0 a, 6,0 Hz), 7,08-7,13 (4H, m), 7.24 to 7,31 (3H, m), 7,63 (1H, d, J=2.0 Hz), to 7.68 (2H, d, J=8,8 Hz), of 8.04 (1H, d, J=6.0 Hz), to 8.62 (1H, Sirs), of 12.26 (1H, c).

ESI-MS (m/z): 563[M+H]+.

Example of getting 338-1

4-(Azetidin-1-yl)piperidine-1-carboxylic acid [4-(4-nitrophenoxy)pyridine-2-yl]amide

Range1H-NMR (CDCl3) δ (ppm): 1,31 (2H, m), 72 (2H, m)2,07 (2H, m), 2,22 (1H, m), 3,06 (2H, m), 3,19 (4H, m)to 3.89 (2H, m), only 6.64 (1H, DD, J=2,0, 5.6 Hz), 7,19 (2H, d, J=9,2 Hz), 7,29 (1H, Sirs), 7,74 (1H, d, J=2.0 Hz), 8,15 (1H, d, J=5.6 Hz), of 8.28 (2H, d, J=9,2 Hz).

ESI-MS (m/z): 398[M+H]+.

Example of getting 338-2

4-(Azetidin-1-yl)piperidine-1-carboxylic acid [4-(4-aminophenoxy)pyridine-2-yl]amide

ESI-MS (m/z): 368[M+H]+.

Example 339

4-(2-Pyrrolidin-1-retil)piperazine-1-carboxylic acid [6-(2-fluoro-4-{3-[2-(4-forfinal)acetyl]touraid}phenoxy)pyrimidine-4-yl]amide

Range1H-NMR (CDCl3) δ (ppm): is 1.81 (4H, m), 2,45-2,67 (10H, m), 2,68 (2H, m), 3,55 (4H, t, J=4,8 Hz), 3,71 (2H, c), 7,00-7,52 (7H, m), of 7.64 (1H, m), 7,86 (1H, DD, J=2,4, and 11.6 Hz), with 8.33 (1H, Sirs), 8,49 (1H, m), 12,38 (1H, Sirs).

ESI-MS (m/z): 625[M+H]+.

Example 340

4-{2-Fluoro-4-[3-(2-phenylacetyl)ureido]phenoxy}-2-{[4-(1-methylpiperazin-4-yl)piperidine-1-yl]carbylamine}pyridine

To a solution of 4-(4-amino-2-pertenece)-2-{[4-(1-methylpiperazin-4-yl)piperidine-1-yl]carbylamine}pyridine (66,2 mg) in tetrahydrofuran (4.0 ml) add a solution of 2-fenilizotsianata in hexane (0,25M, 1.5 ml) at room temperature, followed by stirring overnight. The reaction mixture was concentrated under reduced pressure. Then the obtained residue is purified column chromatography on silica gel (Fuji Silysia NH, eluent: ethyl acetate:methanol = 97:3), getting mentioned in the title compound (49.5 mg, 55%) as white powder.

Range1H-NMR (CDCl3) ´ (ppm): 1,40-of 1.95 (5H, m), 2,32 (3H, c), 2,40 is 2.80 (8H, m), is 2.88 (2H, m in), 3.75 (2H, c), Android 4.04-to 4.15 (2H, m), of 6.52 (1H, DD, J=2,4, 5,6 Hz), 7,10 was 7.45 (8H, m), 7,58-the 7.65 (2H, m), 7,68 (1H, Sirs), 8,03 (1H, d, J=5,6 Hz), 10,57 (1H, Sirs).

ESI-MS (m/z): 590 [M+H]+.

Example 341

4-{2-Fluoro-4-[3-(2-phenylacetyl)ureido]phenoxy}-2-{[4-(1-methylpiperidin-4-yl)piperazine-1-yl]carbylamine}pyridine

To a solution of 4-(4-amino-2-pertenece)-2-{[4-(1-methylpiperidin-4-yl)piperazine-1-yl]carbylamine}pyridine (811 mg) in tetrahydrofuran (50 ml) add a solution of 2-fenilizotsianata in hexane (0,25M, 17 ml) at room temperature, followed by stirring for 5 hours. The reaction mixture is distributed between ethyl acetate and saturated aqueous sodium bicarbonate. The organic layer was washed with saturated saline and dried over anhydrous sodium sulfate. The solvent is evaporated and get the remainder, which is purified column chromatography on silica gel (Fuji Silysia NH, eluent: ethyl acetate ethyl acetate:methanol=97:3). The fractions containing the target compound, concentrate, and get the remainder, which is then suspended in ethyl acetate (8 ml) and hexane (16 ml). The crystals are filtered and dried in a stream of air, getting mentioned in the title compound (629 mg, 61%) as white crystals.

Range1H-NMR (CDCl3) δ (ppm): 1,50-2,10 (6H, m), 2,20-2,40 (4H, m), 2,50-2,60 (4H, m), 2,90-of 3.00 (2H, m), 3,45-3,55 (4H, m in), 3.75 (2H, c), of 6.52 (1H, DD, J=2,4, 56 Hz), 7,10 was 7.45 (8H, m), 7,55-of 7.70 (3H, m), 8,03 (1H, d, J=5.6 Hz), 10,57 (1H, Sirs).

ESI-MS (m/z): 590 [M+H]+.

Example 342

2-{[4-(Dimethylaminomethyl)piperidine-1-yl]carbylamine}-4-{2-fluoro-4-[3-(2-phenylacetyl)ureido]phenoxy}pyridine

To a solution of 4-(4-amino-2-pertenece)-2-{[4-(dimethylaminomethyl)piperidine-1-yl]carbylamine}pyridine (62,7 mg) in tetrahydrofuran (4.0 ml) add a solution of 2-fenilizotsianata in hexane (0,25M, 1.6 ml) at room temperature, followed by stirring overnight. The reaction mixture was concentrated under reduced pressure. The resulting residue is then purified column chromatography on silica gel (Fuji Silysia NH, eluent: ethyl acetate), obtaining specified in the header connection (48,0 mg, 54%) as white powder.

Range1H-NMR (CDCl3) δ (ppm): of 1.10-1.20 (2H, m), of 1.65 (1H, m), 1,75-of 1.85 (2H, m), 2,10-of 2.15 (2H, m), of 2.23 (6H, c), 2,80-2,90 (2H, m in), 3.75 (2H, c), 4,00-4,10 (2H, m), of 6.52 (1H, DD, J=2,4, 5,6 Hz), 7,10 was 7.45 (8H, m), 7,60-the 7.65 (2H, m), 8,03 (1H, Sirs), 8,30 (1H, d, J=5.6 Hz), of 10.58 (1H, Sirs).

ESI-MS (m/z): 549 [M+H]+.

Example 343

4-(2-Fluoro-4-{3-[2-(4-forfinal)acetyl]ureido}phenoxy)-2-{[4-(1-methylpiperazin-4-yl)piperidine-1-yl]carbylamine}pyridine

To a solution of 4-(4-amino-2-pertenece)-2-{[4-(1-methylpiperazin-4-yl)piperidine-1-yl]carbylamine}pyridine (71 mg) in tetrahydrofuran (2.0 ml) add a solution of 2-(4-forfinal)acetylacetonate in tetrahydrofuran (0,25M, 1.65 ml) at room temperature to follow them by stirring for 3 days. The reaction mixture was concentrated under reduced pressure. The resulting residue is purified column chromatography on silica gel (Fuji Silysia NH, eluent: ethyl acetate:methanol = 97:3), receiving specified in the header connection (7,1 mg, 7.1%) in the form of white powder.

Range1H-NMR (CDCl3) δ (ppm): 1,40-of 1.95 (5H, m), a 2.36 (3H, c), 2,40 is 2.80 (8H, m), is 2.88 (2H, m), of 3.73 (2H, c), Android 4.04-to 4.15 (2H, m), of 6.52 (1H, DD, J=2,4, 5,6 Hz), 7,00-7,30 (7H, m), EUR 7.57 to 7.62 (2H, m), 7,86 (1H, m), 8,03 (1H, d, J=5.6 Hz), 10,53 (1H, Sirs).

ESI-MS (m/z): 608 [M+H]+.

Example 344

4-(4-{3-[2-(4-Forfinal)acetyl]ureido}phenoxy)-2-{[4-(1-methylpiperazin-4-yl)piperidine-1-yl]carbylamine}pyridine

To a solution of 4-(4-aminophenoxy)-2-{[4-(1-methylpiperazin-4-yl)piperidine-1-yl]carbylamine}pyridine (86,9 mg) in tetrahydrofuran (2.5 ml) add a solution of 2-(4-forfinal)acetylacetonate in tetrahydrofuran (0,25M, 2,12 ml) at room temperature, followed by stirring for 3 days. The reaction mixture was concentrated under reduced pressure. The resulting residue is purified column chromatography on silica gel (Fuji Silysia NH, eluent: ethyl acetate:methanol = 97:3), receiving specified in the header connection (22,5 mg, 18%) as white powder.

Range1H-NMR (CDCl3) δ (ppm): 1,40-of 1.95 (5H, m), of 2.34 (3H, c), 2,40 is 2.80 (8H, m), is 2.88 (2H, m), and 3.72 (2H, c), 4,05-to 4.15 (2H, m), 6,51 (1H, DD, J=2,4, 5,6 Hz), 7,00-to 7.35 (7H, m), 7,50-rate of 7.54 (2H, m), 7,58 (1H, d, J=2.4 Hz), 7,78 (1H, Sirs), 8,02 (1H, d, J=5.6 Hz), 10,43 (1H, Sirs).

ESI-MS m/z: 590 [M+H] +.

Example 345

4-(2-Fluoro-4-{3-[2-(4-forfinal)acetyl]ureido}phenoxy)-2-{[4-(1-methylpiperidin-4-yl)piperazine-1-yl]carbylamine}pyridine

To a solution of 4-(4-amino-2-pertenece)-2-{[4-(1-methylpiperidin-4-yl)piperazine-1-yl]carbylamine}pyridine (81,2 mg) in tetrahydrofuran (2.0 ml) add a solution of 2-(4-forfinal)acetylacetonate in tetrahydrofuran (0,25M, 1.9 ml) at room temperature, followed by stirring for 3 days. The reaction mixture was concentrated under reduced pressure. The resulting residue is then purified column chromatography on silica gel (Fuji Silysia NH, eluent: ethyl acetate:methanol = 97:3 to 95:5), receiving specified in the title compound (9.7 mg, 8.5 percent) in the form of white powder.

Range1H-NMR (CDCl3) δ (ppm): 1,50-2,10 (6H, m), 2,20-2,40 (4H, m), 2,50-2,60 (4H, m), 2,90-3,10 (2H, m), 3,45-3,55 (4H, m), of 3.73 (2H, c), of 6.52 (1H, DD, J=2,4, 5,6 Hz), 7,00-7,30 (7H, m), to 7.59-of 7.70 (2H, m), to 7.77 (1H, m), 8,03 (1H, d, J=5.6 Hz), 10,53 (1H, Sirs).

ESI-MS (m/z): 608 [M+H]+.

Example 346

4-(4-{3-[2-(4-Forfinal)acetyl]ureido}phenoxy)-2-{[4-(1-methylpiperidin-4-yl)piperazine-1-yl]carbylamine}pyridine

To a solution of 4-(4-aminophenoxy)-2-{[4-(1-methylpiperidin-4-yl)piperazine-1-yl]carbylamine}pyridine (834 mg) in tetrahydrofuran (45 ml) add a solution of 2-(4-forfinal)acetylacetonate in ethyl acetate (0,25M, 15 ml) at room temperature, followed by stirring for 3.5 hours. The reaction mixture is dissolved, and edalat between ethyl acetate and saturated aqueous sodium bicarbonate. The organic layer was washed with saturated saline and dried over anhydrous sodium sulfate. The solvent is evaporated and get the remainder, which is purified column chromatography on silica gel (Fuji Silysia NH, eluent: ethyl acetate, then ethyl acetate:methanol = 97:3). The fractions containing the target compound, concentrate, and get the remainder, which is then suspended in ethyl acetate (8 ml) and hexane (16 ml). The crystals are filtered and dried in a stream of air, getting mentioned in the title compound (546 mg, 49%) as white crystals.

Range1H-NMR (CDCl3) δ (ppm): 1,50-2,02 (6H, m), 2,22-of 2.34 (4H, m), 2,54-2,62 (4H, m), 2,88-2,96 (2H, m), 3,44-of 3.54 (4H, m), and 3.72 (2H, c), 6,51 (1H, DD, J=2,4, 5,6 Hz), 7,00-7,30 (7H, m), 7,50-rate of 7.54 (2H, m), 7,60 (1H, d, J=2,4 Hz), 8,02 (1H, d, J=5.6 Hz), of 8.27 (1H, Sirs), of 10.47 (1H, Sirs).

ESI-MS (m/z): 590 [M+H]+.

Example 347

2-{[4-(Dimethylaminomethyl)piperidine-1-yl]carbylamine}-4-(2-fluoro-4-{3-[2-(4-forfinal)acetyl]ureido}phenoxy)pyridine

To a solution of 4-(4-amino-2-pertenece)-2-{[4-(dimethylaminomethyl)piperidine-1-yl]carbylamine}pyridine (61,1 mg) in tetrahydrofuran (2.0 ml) add a solution of 2-(4-forfinal)acetylacetonate in tetrahydrofuran (0,25M, 1.6 ml) at room temperature, followed by stirring for 3 days. The reaction mixture is distributed between ethyl acetate and saturated aqueous sodium bicarbonate. The organic layer is washed with NASA the military saline and dried over anhydrous sodium sulfate. The solvent is evaporated and get the remainder, which is purified column chromatography on silica gel (Fuji Silysia NH, eluent: ethyl acetate), obtaining mentioned in the title compound (13.3 mg, 15%) as white powder.

Range1H-NMR (CDCl3) δ (ppm): 1,10-1,25 (2H, m), of 1.65 (1H, m), 1,75-1,90 (2H, m), 2,10-of 2.30 (8H, m), 2,80-2,90 (2H, m), and 3.72 (2H, c), 4,00-4,10 (2H, m), of 6.52 (1H, DD, J=2,4, 5,6 Hz), 7,10-7,30 (7H, m), to 7.59-to 7.64 (2H, m), of 7.95 (1H, Sirs), 8,03 (1H, d, J=5.6 Hz), 10,54 (1H, Sirs).

ESI-MS (m/z: 567 [M+H]+.

Example 348

2-{[4-(Dimethylaminomethyl)piperidine-1-yl]carbylamine}-4-(4-{3-[2-(4-forfinal)acetyl]ureido}phenoxy)pyridine

To a solution of 4-(4-aminophenoxy)-2-{[4-(dimethylaminomethyl)piperidine-1-yl]carbylamine}pyridine (61,8 mg) in tetrahydrofuran (2.0 ml) add a solution of 2-(4-forfinal)acetylacetonate in tetrahydrofuran (0,25M, 1.7 ml) at room temperature, followed by stirring for 3 days. The reaction mixture is distributed between ethyl acetate and saturated aqueous sodium bicarbonate. The organic layer was washed with saturated saline and dried over anhydrous sodium sulfate. The solvent is evaporated and get the remainder, which is purified column chromatography on silica gel (Fuji Silysia NH, eluent: ethyl acetate), obtaining specified in the header connection (32,6 mg, 36%) as white powder.

Range1H-NMR (CDCl3) δ (ppm): 1,15-1,25 (2H, m), of 1.65 (1H, m, 1,70-1,80 (2H, m), 2,10-of 2.30 (8H, m), 2,80-2,90 (2H, m), and 3.72 (2H, c), 4,00-4,10 (2H, m), 6,50 (1H, DD, J=2,4, 5,6 Hz), 7,00-7,30 (7H, m), 7,50-rate of 7.54 (2H, m), 7,60 (1H, d, J=2.4 Hz), 7,94 (1H, m), 8,02 (1H, d, J=5.6 Hz), 10,44 (1H, Sirs).

ESI-MS (m/z): 549 [M+H]+.

Example 349

4-(Pyrrolidin-1-ylmethyl)piperidine-1-carboxylic acid [6-(2-fluoro-4-{3-[2-(4-forfinal)acetyl]touraid}phenoxy)pyrimidine-4-yl]amide

6-(2-Fluoro-4-nitrophenoxy)pyrimidine-4-ylamine (200 mg) is dissolved in tetrahydrofuran (8 ml) under nitrogen atmosphere and then add triethylamine (0,334 ml) and phenylcarbamate (0,301 ml), cooling in a bath containing ice water, and then heated to room temperature and stirred for 1.5 hours. The reaction mixture is distributed between ethyl acetate (200 ml) and saturated aqueous sodium hydrogen carbonate (50 ml). The organic layer was washed with saturated aqueous sodium hydrogen carbonate (50 ml), water (50 ml) and saturated saline (100 ml) in that order, then dried over anhydrous sodium sulfate. The solvent is evaporated and get the remainder, to which is added N,N-dimethylformamide (8 ml). Then add dihydrochloride 4-(pyrrolidin-1-ylmethyl)piperidine (771 mg) and triethylamine (0,896 ml) followed by stirring for 4 hours. The reaction mixture is distributed between ethyl acetate (100 ml) and saturated aqueous ammonium chloride (50 ml). The organic layer was washed with saturated in the s ' solution of ammonium chloride (50 ml), water (50 ml)and saturated saline (50 ml) in that order, then dried over anhydrous sodium sulfate. The solvent is evaporated and get the remainder, which is purified column chromatography on silica gel (Fuji Silysia NH, heptane:ethyl acetate = 1:1, then ethyl acetate). The fractions containing the target compound, concentrate, and get 4-(pyrrolidin-1-ylmethyl)piperidine-1-carboxylic acid [6-(2-fluoro-4-nitrophenoxy)pyrimidine-4-yl]amide (350 mg) in the form of oil pale yellow color.

4-(Pyrrolidin-1-ylmethyl)piperidine-1-carboxylic acid [6-(2-fluoro-4-nitrophenoxy)pyrimidine-4-yl]amide (350 mg) was dissolved in tetrahydrofuran (8 ml) and methanol (8 ml) and then added 10% palladium on coal (162 mg), followed by stirring in an atmosphere of hydrogen for 6 hours. The reaction mixture is filtered to remove the catalyst. The filtrate is concentrated under reduced pressure, obtaining a residue, which is purified column chromatography on silica gel (eluent: ethyl acetate:methanol = 9:1). The fractions containing the target compound, concentrate, and get the crude 4-(pyrrolidin-1-ylmethyl)piperidine-1-carboxylic acid [6-(4-amino-2-pertenece)pyrimidine-4-yl]amide (201,4 mg) as a foam pale yellow color.

4-(Pyrrolidin-1-ylmethyl)piperidine-1-carboxylic acid [6-(4-amino-2-pertenece)pyrimidine-4-yl]amide (100 mg) is dissolved in ethanol (1.0 ml) in the atmosphere is fere nitrogen and then added (S)-(+)-10-camphorsulfonic acid (56 mg), followed by stirring for 5 minutes Add 0,25M solution of 2-(4-forfinal)acety