New aminopyrimidine derivatives as plk1 inhibitors

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to to new compounds of formula (1) or their pharmaceutically acceptable salts, optionally in the form of (1S)-isomers showing the properties of polo-like kinase (serine-threonine kinase) PLK1 inhibitor. In the compounds of formula (1) , R1 represents a halogen atom; a lower alkyl group having 1-2 carbon atoms, which can be substituted by 3 fluorine atoms; or a cyclopropyl group; R2 represents a hydrogen atom; one of R3 and R4 represents a hydrogen atom while the other one of R3 and R4 represents: a) a lower alkyl group substituted by NRaRb wherein each Ra and Rb, which can be identical or different, represent a lower alkyl group, or each Ra and Rb, which can be different, represent a hydrogen atom, a lower alkyl group or a cycloalkyl group having 3-6 carbon atoms wherein a cycloalkyl group can be substituted by one ore more substitutes which can be identical or different and specified in a group 1): a lower alkyl; b) a 4-6-member aliphatic heterocyclic group specified in an azetidinyl group, a pyrrolidinyl group and a piperidinyl group; c) a lower alkyl group substituted by a 4-6-member aliphatic heterocyclic group specified in an azetidinyl group, a pyrrolidinyl group and a piperidinyl group; d) a 6-member aromatic heterocyclic group specified in a pyridyl group wherein each of an aliphatic heterocyclic group and an aromatic heterocyclic group can be substituted by substitutes specified in a group 1) described above; R5 represents a hydrogen atom, a cyano group, a halogen atom or a lower alkyl group.

EFFECT: compounds can find application in treating oncological diseases.

10 cl, 4 dwg, 8 tbl, 42 ex

 

The technical field to which the invention relates

The present invention relates to new substituted derivative of aminopyrimidine, which inhibits proliferation of tumor cells on the basis of the inhibitory effect against PLK1, showing through this anti-tumor effect, which may find application in medicine; and to the PLK1 inhibitor and antitumor agent containing the derivative.

Prior art

Proliferation is known to be generally active in cancer cells compared with normal cells, and in many cases it is believed that the disorder of cell proliferation due to anomalies of the mechanism of cell cycle regulation is a cause of cancer. Mitotic phase (M phase) of the cell cycle is a phase equal to the separation of chromosomes into daughter cells and exact regulation of the process is essential for the proliferation and survival of cells. It is therefore considered that the inhibition of progression of M phase is an effective means of inhibiting cell proliferation, and in practice, antineoplastic agents, aimed at M phase, such as Taxol, vincristine, or the like, has achieved a clinically effective results.

It was known that many of the stages in the course of M phase is regulated by protein kinases, which fo is TRILLIUM proteins. Family PLK (Polo-like kinase is a kinase serine-threonine, which plays an important role in cell cycle regulation, including M phase, and this family includes 4 identical protein PLK1, PLK2, PLK3 and SAK (Nature. Review. Molecular. Cell Biology (Nat. Rev. Mol. Cell Biol.), Vol. 5, 429, (2004)). It is known that PLK1 is involved in many important stages of M phase in mammalian cells: it was reported that PLK1 is involved in every stage of entry into M phase, regulation of the centrosome, the separation of the chromosomes and cytokines, the phosphorylation of various substrates (Nature. Review. Molecular. Cell Biology (Nat. Rev. Mol. Cell Biol.), Vol. 5, 429, (2004)).

In addition, there are many messages, indicating that PLK1 redundantly expressed in various cancer tissues in humans. For example, it is shown that PLK1 redundantly expressed in non-small cell lung cancer (Oncogene, Vol. 14, 543, (1997)) and head and neck cancer (Cancer Research, Vol. 15, 2794, (1999)), and there are data showing that overexpression of PLK1 is associated with prognosis in patients with these diseases. It is also reported that the expression of PLK1 increased in other types of cancer, such as colon cancer, esophageal cancer, ovarian cancer and melanoma. These messages indicate that overexpression of PLK1 is associated with one or another malignant alteration of cells, and that the function of PLK1 important, in particular, when applying M phase in cancer cells

On the basis of these facts, it is believed that PLK1 is a possible target for anticancer approach. Indeed, there are many reports of experiments on the study of inhibitory effect on the function of PLK1 against cancer cells by using different experimental techniques. For example, it is reported that in the experiment of ekspressirovali functionally inhibited PLK1 mutant in cells by use of a viral vector, inhibition of PLK1 stimulates selective apoptosis of cancer cells (Cell growth &Differentiation (Cell growth &Diff.), Vol. 11, 615, (2000)). There is also a message that indicates that siPHK PLK1 induces growth inhibition and apoptosis of cancer cells (Journal of the National Cancer Institute (J. Natl. Cancer Inst.), Vol. 94, 1863 (2002)). In addition, it is reported that shPHK PLK1 (Journal of the National Cancer Institute (J. Natl. Cancer Inst.), Vol. 96, 862 (2004)) or antisense oligonucleotide (Oncogene, Vol. 21, 3162 (2002)) gives the antitumor effect on the model of xenograft tumors in mice. These experimental results show that inhibition of PLK1 activity stimulates growth inhibition and apoptosis of cancer cells and strong evidence that the PLK1 inhibitor is an effective antitumor agent.

The applicants filed a patent application for substituted derivative of imidazole, providing inhibiting PLK1 effect (international publication WO2006025567).

Description of the invention

The aim of the present invention is to provide a new derived aminopyrimidine that manifests inhibiting PLK1 effect and excellent cytotoxic (cell growth inhibitory activity, based on the inhibitory effect, and through this to develop an antitumor agent based on such PLK1 inhibition effect.

To achieve this goal, the applicants have synthesized a wide range of derivative aminopyrimidine and found that the compound represented by the formula [I], shows the superior inhibiting PLK1 effect and cytotoxic activity, based on the inhibitory effect, and thus was established the present invention.

That is, the present invention relates to a compound represented by the formula [I]:

where each R1and R2that may be the same or different, represents a hydrogen atom; a halogen atom; the group of lower alkyl having 1-2 carbon atoms which may be substituted by 1-3 fluorine atoms; or cyclopropyl group;

one of R3and R4represents a hydrogen atom while the other of R3and R4is:

(a) the group of lower alkyl, substituted NRaRbwhere each Raand Rbthat may be one the same or different, represent a hydrogen atom, a group of lower alkyl, benzyl group or cycloalkyl group having 3-6 carbon atoms, where cycloalkyl group may be substituted by one or more substituents, which may be the same or different, selected from the following compounds PP. 1-3:

1) the group of lower alkyl;

2) Deputy selected from <group Deputy β>; and

3) the group of lower alkyl, substituted by one or more substituents selected from <group Deputy β>; and cycloalkyl group may include an unsaturated bond;

b) 4-6-membered aliphatic heterocyclic group selected from azetidine group, pyrrolidinyl group, piperidinyl group and piperazinilnom group;

c) the group of lower alkyl, substituted 4-6-membered aliphatic heterocyclic group selected from azetidine group, pyrrolidinyl group, piperidinyl group and piperazinilnom group;

d) 5 - or 6-membered aromatic heterocyclic group selected from pyrrolidino group, imidazolidine group, pyrazolidine group, peredelnoj group, personalni group and pyrimidinyl group; or

e) the group of lower alkyl, substituted 5 - or 6-membered aromatic heterocyclic group selected from pyrrolidino group, imidazolidine group, a pyrazole the school group, peredelnoj group, personalni group and pyrimidinyl group, where each of the aliphatic heterocyclic group and aromatic heterocyclic group independently may be substituted by one or more substituents, which may be the same or different, selected from the following compounds PP. 1-4:

1) the group of lower alkyl;

2) Deputy selected from <group Deputy β>;

3) the group of lower alkyl, substituted by one or more substituents selected from <group Deputy β>; and

4) cycloalkyl group having 3-6 carbon atoms that may be substituted by one or more substituents selected from <group Deputy β>;

R5represents a hydrogen atom, a cyano, a halogen atom or a group of the lower alkyl; and

<Group Deputy β> is as defined below:

<Group Deputy β>: halogen atom, a hydroxy-group, a nitrogroup, cinegroupe, amino group, carnemolla group, aminosulfonyl group, aminogroup, the group of lower alkylsulfonyl, the group lower alkylsulfonyl, group, lower alkoxy group lower alkoxycarbonyl, the group lower alkoxycarbonyl, the group of lower alkanoyl, the group lower alkanoyloxy, the group lower alkylthio, carboxyl group and benzyl group;

or headlamp is asepticheski acceptable salt or complex ether.

The connection represented by the above formula (I)includes all existing enantiomers and diastereoisomers, in addition to the racemates of the compounds.

The invention also relates to a combined preparation for simultaneous, separate or sequential injection in the treatment of cancer, where the combined product includes 2 separate preparation:

• preparation comprising, together with a pharmaceutically acceptable carrier or diluent, the compound represented by the formula [I]or its pharmaceutically acceptable salt or ester; and

• preparation comprising, together with a pharmaceutically acceptable carrier or diluent antitumor agent selected from the group consisting of antitumor alkylating funds, antitumor antimetabolites, antitumor antibiotics, anticancer agents of plant origin, antitumor of platinum complex compounds, antitumor derivative camptothecin, antitumor of inhibitron tyrosine kinases, monoclonal antibodies, interferons, biological response modifiers, and other anticancer agents, or their pharmaceutically acceptable salt, or a complex ester,

where antineoplastic alkylating form the N-oxide nitrogen mustard, cyclophosphamide, ifosfamide, IU is falan, the busulfan, mitobronitol, carboxine, thiotepa, ranimustine, nimustine, temozolomide, carmustine;

antineoplastic antimetabolites are methotrexate, 6-mercaptopurine riboside, mercaptopurine, 5-fluorouracil, tegafur, doxifluridine, carmofur, cytarabine, cytarabine ocfosfate, enocitabine, S-1, gemcitabine, fludarabine and pemetrexed disodium;

antitumor antibiotics are of actinomycin D, doxorubicin, daunorubicin, neocarzinostatin, bleomycin, peplomycin, mitomycin C, aclarubicin, pirarubicin, epirubicin, zinostatin stimulater, idarubitsin, sirolimus and valrubicin;

anti-cancer drugs of plant origin are vincristine, vinblastine, vindesine, etoposide, sobuzoxane, docetaxel, paclitaxel and vinorelbine;

antitumor complex platinum compounds are cisplatin, carboplatin, nedaplatin and oxaliplatin;

antitumor derivatives of camptothecin are irinotecan, topotecan and camptothecin;

antitumor inhibitors of tyrosine kinases represent gefitinib, imatinib and erlotinib;

monoclonal antibodies are cetuximab, bevacizumab, rituximab, alemtuzumab and trastuzumab;

interferons are interferon α, interferon α-2A, interferon α-2b, interferon-β, interferon γ-1A, and interferon γ-n1;

option is Katori biological reactions are christening, lentinan, sizofiran, picibanil and ubenimex; and

other antineoplastic represent mitoxantrone, L-asparaginase, procarbazine, dacarbazine, hydroxycarbamide, pentostatin, tretinoin, alefacept, darbepoietin Alfa, anastrozole, exemestane, bikalutamid, leiprorelina, flutamide, fulvestrant, pegaptanib of Octanate, denileukin diftitox, aldesleukin, thyrotropin alpha, arsenic trioxide, bortezomib, capecitabine, goserelin.

In addition, the invention relates to a pharmaceutical composition comprising, together with a pharmaceutically acceptable carrier or diluent, the compound represented by the formula [I]or its pharmaceutically acceptable salt or ester; and an antitumor agent selected from the group consisting of antitumor alkylating funds, antitumor antimetabolites, antitumor antibiotics, anticancer agents of plant origin, antitumor of platinum complex compounds, antitumor derivative camptothecin, antitumor inhibitors of tyrosine kinases, monoclonal antibodies, biological response modifiers, and other anticancer agents (where the definition of each antitumor agents has the same meaning as defined above), or their pharmaceutically acceptable salt or complex EPE is.

The invention also relates to methods for treating cancerous lesions, including simultaneous, separate or sequential introduction of a therapeutically effective amount of the compounds represented by the above formula [I]or its pharmaceutically acceptable salt or a complex ester, in combination with a therapeutically effective amount of anti-cancer agents selected from the group consisting of antitumor alkylating funds, antitumor antimetabolites, antitumor antibiotics, anticancer agents of plant origin, antitumor of platinum complex compounds, antitumor derivative camptothecin, antitumor inhibitors of tyrosine kinases, monoclonal antibodies, interferons of biological response modifiers, and other anticancer agents (where the definition of each antitumor agents has the same meaning as defined above), or their pharmaceutically acceptable salt, or a complex ester.

The invention also relates to an inhibitor of PLK1 to obtain drugs for the treatment of cancer and PLK1 inhibitor in combination with an antitumor agent to obtain drugs for cancer treatment. In addition, the invention relates to a method for the treatment of cancerous lesions in mammals is apicauda (in particular, people), which includes the introduction of a mammal a therapeutically effective amount of an inhibitor of PLK1, and to a method for the treatment of cancerous lesions in mammals (particularly humans), which includes the introduction of a mammal a therapeutically effective amount of an inhibitor of PLK1, in combination with a therapeutically effective amount of anti-cancer drugs.

In addition, the invention relates to a tool for the treatment of cancerous lesions, including PLK1 inhibitor as an active ingredient, and a means for the treatment of cancerous lesions, which contains, together with the anticancer agent, the PLK1 inhibitor as an active ingredient.

Next will be explained the symbols and terms described in this document.

"The group of lower alkyl" in the above formula (I) refers to remotemachine or branched alkylenes group having 1-6 carbon atoms, and its examples include methyl group, ethyl group, through the group, isopropyl group, boutelou group, isobutylene group, sec-boutelou group, tert-boutelou group, pentelow group, hexoloy group and the like.

"Cycloalkyl group" in the above formula (I) refers to a 3-8-membered acyclically group, and examples of it include cyclopropyl group, cyclobutyl group, cyclopen the ilen group, tsiklogeksilnogo group, cycloheptyl group, cyclooctyl group and the like, and, preferably, refers to a 3-6-membered acyclically group. Preferred examples include cyclopropyl group, cyclobutyl group, cyclopentyl group and tsiklogeksilnogo group.

"Aliphatic heterocyclic group" in the above formula (I) refers to a saturated or unsaturated aliphatic heterocyclic group, generally having at least one atom selected from a nitrogen atom, oxygen atom and sulfur atom in addition to carbon atoms, i.e., mono -, di - or tricyclic condensed ring. Examples include azetidinol group, pyrrolidinyl group, piperidinyl group, piperazinilnom group, morpholinopropan, tetrahydropyranyloxy group, imidazolidinyl group, thiomorpholine, tetrahydropyridine group, tetrahydroisoquinoline group and the like. "4-6-membered aliphatic heterocyclic group" in the above formula (I) refers to a saturated or unsaturated aliphatic heterocyclic group, which is a 4-6-membered monocyclic ring, and examples include azetidinol group, pyrrolidinyl group, piperidinyl group, piperazinilnom group and the like.

"Aromatichydrocarbons group" in the above formula (I) in General refers to a heterocyclic group with aromatic properties, containing at least one heteroatom such as nitrogen atom, oxygen atom or the like, and examples include a 5-7-membered monocyclic heterocyclic group and heterocyclic group condensed ring formed by the merger 3-8-membered ring with a monocyclic heterocyclic group, and the like. In particular, can be specified thienyl group, pyrrolidine group, furilla group, thiazolidine group, imidazolidinyl group, pyrazolidine group, oxazoline group, Peregrina group, piratininga group, pyrimidinyl group, pyridazinyl group, isoxazolyl group, izochinolina group, isoindolyl group, indazolinone group, indayla group, khinoksalinona group, kinolinna group, benzoimidazolyl group, benzofuranyl group and the like. "5 - or 6-membered aromatic heterocyclic group" in the above formula (I) in General refers to 5 - or 6-membered monocyclic heterocyclic group with aromatic properties, and its examples include pyrrolidinyl group, imidazolidinyl group, pyrazolidine group, pyridyloxy group, personilnya group, pyrimidinyl group and the like.

"Halogen atom" in the above formula (I) may be illustrated by a fluorine atom, a chlorine atom, atomo is bromine, the iodine atom and the like, and among them, for example, the preferred fluorine atom, chlorine atom and bromine atom.

"The group of lower alkylsulfonyl" in the above formula (I) refers to the Deputy, formed by binding the above "group of lower alkyl" with the sulfur atom sulfonyloxy group, and its examples include methylsulfonyl group, ethylsulfonyl group, butylsulfonyl group and the like.

"Group lower alkylsulfonyl" in the above formula (I) refers to the Deputy, formed by N-substitution of the above "group lower alkylsulfonyl" in the amino group, and examples of it include methylsulfonylamino, ethylsulfonylimidazo, butylsulfonyl and the like.

"The group of lower alkoxy" in the above formula (I) refers to a group formed by linking the "group of lower alkyl" is an oxygen atom, and examples include a methoxy group, ethoxypropan, propoxylate, isopropoxy, butoxypropyl, isobutoxy, sec-butoxypropyl, tert-butoxypropyl, pentyloxy, neopentylene, hexyloxy, isohexadecane and the like.

"The group of lower alkoxycarbonyl" in the above formula (I) refers to a group formed by linking the "group of lower alkoxy" with carbonyl group is, and its specific examples include methoxycarbonyl group, ethoxycarbonyl group, propoxycarbonyl group, isopropoxycarbonyl group, butoxycarbonyl group, isobutoxyethanol group, sec-butoxycarbonyl group, tert-butoxycarbonyl group, ventilatsioonile group, neopentylglycol group, hexyloxymethyl group, isohexadecane group and the like.

"Group lower alkoxycarbonyl" in the above formula (I) refers to a group formed by N-substitution of the above "group lower alkoxycarbonyl" in the amino group, and specific examples include methoxycarbonylamino, ethoxycarbonylmethoxy, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonylamino, isobutoxyethanol, sec-butoxycarbonylamino, tert-butoxycarbonylamino, ventilatsiooniinseneride, neopentecostalism, getselectionrange, isohexadecane and the like.

"The group of lower alkanoyl" in the above formula (I) refers to a group formed by linking the "group of lower alkyl" with carbonyl group, and preferably represents a group in which an alkyl group having 1-5 carbon atoms is kind, linked to the carbonyl group. For example, there may be mentioned acetyl group, propylaniline group, Butyrina group, isobutylene group, valerina group, isovaleryl group, Privolnaya group, pantaneira group and the like.

"Group lower alkanoyloxy" in the above formula (I) refers to a group formed by linking the "group of lower alkanol with an oxygen atom, and examples include acetyloxy, propionyloxy, butyryloxy, isobutyryloxy, valeriansoup, isovaleraldehyde, pivaloyloxy, partnershop and the like.

"Group lower alkylthio" in the above formula (I) refers to the Deputy, formed by the linkage group of the lower alkyl" with the sulfur atom, and examples include metalcorp, ethylthiourea, butylthiourea and the like.

The term “PLK” is prepodobnyy kinase.

The term “PLK1” is one of the family members PLK (Polo-like kinase), composed of PLK1, PLK2, PLK3 and SAK.

The term “inhibitor of PLK1” is a drug for the inhibition of Polo-like kinase 1.

The terms "pharmaceutically acceptable salt or ester" and "pharmaceutically acceptable carrier or diluent will be explained later.

Used in the present description Ter is in the "cancer treatment" means the inhibition of growth of cancer cells by the introduction of anti-cancer tool in patients suffering from cancer. The treatment preferably inhibits the growth of cancer cells, i.e. it reduces the size of the tumor, which can be measured. Treatment is preferable to completely eradicate the cancer.

Used in the present description, the term "cancer" includes solid tumors and cancerous lesions of the hematopoietic system. Examples of solid tumors include brain cancer, head and neck cancer, esophageal cancer, thyroid cancer, small cell lung cancer, non-small cell lung cancer, breast cancer, stomach cancer, cancer of the gall bladder/bile duct, liver cancer, pancreatic cancer, colon cancer, rectal cancer, ovarian cancer, chorioepithelioma, uterine cancer, cervical cancer, cancer of the renal pelvis/ureter, bladder cancer, prostate cancer, penile cancer, testes cancer, embryonal cancer, Wilms tumor, skin cancer, malignant melanoma, neuroblastoma, osteosarcoma, abnormal Ewing sarcoma, soft tissue sarcoma and the like. Examples of cancerous lesions of the hematopoietic system include acute leukemia, chronic lymphocytic leukemia, chronic myelogenous leukemia, true polycythemia, malignant lymphoma, multiple myeloma, non-Hodgkins lymphoma and the like.

Used in the present description, the term "drug" includes oral medications and parenteral preparation oral drugs are tablet capsule, powder, granule or the like, preferably a tablet, capsule or the like. Examples of parenteral drug are sterilized liquid medication, such as solution, suspension and the like, which, in particular, are injectable drug, a drug for drip infusion and the like, and preferably represents a preparation for intravenous injection and intravenous drip.

Used in the present description, the term "a combined preparation" refers to the drug, including 2 or more for simultaneous, separate or sequential injection in the treatment, which may be provided in the form of a drug or pharmaceutical composition of the set type. "Combined product" also includes preparations obtained additional combination of one or more drugs with the above-described combination drug that includes 2 separate product that can be used in the treatment of cancer.

In addition to the two separate drugs, one or more drugs including at least one antitumor agent selected from the group consisting of antitumor alkylating funds, antitumor antimetabolites, antitumor antibiotics, anticancer agents plant origin is of, antitumor of platinum complex compounds, antitumor derivative camptothecin, antitumor of inhibitron tyrosine kinases, monoclonal antibodies, interferons, biological response modifiers, and other anticancer agents (where the definition of each antitumor agents has the same meaning as defined above), or their pharmaceutically acceptable salt, or a complex ester, may also be combined, together with a pharmaceutically acceptable carrier or diluent. In this case, additional combined at least one drug may be administered simultaneously, separately or sequentially with two separate drugs. Combined preparation containing three drugs can be illustrated by the preparation containing the compound represented by the above formula (I); preparation containing 5-fluorouracil, and a preparation containing leucovorin.

For the combined drug both of the individual drugs may represent either oral or parenteral preparation, or alternatively, one of the two individual drugs may present oral drug, whereas other medication is parenteral medication (injectable drug or medication for drip infusion).

For the "drug" ACC is accordance with the invention, therapeutically effective amount of the compounds according to the invention can be incorporated together with a pharmaceutically acceptable carrier or diluent. It is believed that used the techniques of drafting common for specialists in this area and therefore well known. Preferably, such a drug together with a pharmaceutically acceptable carrier or diluent may be formed into a preparation for oral administration, intravenous infusion or injection, using a variety of methods well-known to specialists in this field.

Used in the present description, the term "introduction" includes parenteral and/or oral administration in the case of the combined preparation according to the invention. That is, when the introduction of combination drug both components may be injected parenterally, or one may be injected parenterally, while the other is administered orally, or otherwise, both can be administered orally. In the present description "parenteral administration" includes, for example, intravenous, intramuscular and the like, and preferably includes intravenous. With the introduction of three or more drugs in combination at least one drug may be introduced parenterally, preferably administered intravenously, and preferably, is introduced intravenous drip infusion or intravenous injection. In addition, for the case of the introduction of three or more preparatov any combination of the drugs may submit oral or parenteral drug drug.

When implementing the invention, the compound represented by the above formula (I)may be administered concomitantly with other anti-tumor agent. Also, at first it may be a compound represented by the above formula (I), and in the future may be another anti-cancer agent, or alternatively, the first may be another anti-cancer agent, and in the future may be a compound represented by the above formula (I). In addition, you can enter the connection represented by the above formula (I), and then separately at time intervals may be another anti-cancer agent, or alternatively, may be another anti-cancer agent, and then separately over the time interval may be a compound represented by the above formula (I). Specialists in this field can appropriately choose the order and interval of administration, depending on the drug used, including the connection represented by the above formula (I), of the drug, including antitumor agent, which can be used in combination type of cancer cells to be treated, and the condition of the patient.

Used in the present description, the term "simultaneously" means the introduction at the same time the La treatment. The term "separately" means the introduction separately at different times for treatment and, for example, he refers to the case where one drug is applied on the first day, and the other medication is the next day for treatment. The term "sequentially" means the introduction of order and, for example, he refers to the case where first used one drug, and then used to treat medicine after a preset time interval.

Used in the present description, the term "antitumor alkylating funds" means an alkylating agent with antitumor activity, and in the present description "alkylating agent" generally refers to the means of ensuring the alkyl group in the alkylation reaction of an organic compound in which a hydrogen atom is substituted by an alkyl group. Examples of antitumor alkylating funds" include the N-oxide nitrogen mustard, cyclophosphamide, ifosfamide, melphalan, busulfan, mitobronitol, Carbogen, thiotepa, ranimustine, nimustine, temozolomide, carmustine and the like.

The term "antineoplastic antimetabolites used in the present description, refers to a metabolic antagonist with antitumor activity, and in the present description "metabolites.reactions" in a broad sense includes substances implemented in normal metabolic change that must occur because of their similar structure or function with metabolites (vitamins, coenzymes, amino acids, sugars etc), which are important factors in the body, and substances that prevent the production of high-energy intermediates, inhibition of the transport of electrons. Examples of antineoplastic antimetabolites include methotrexate, 6-mercaptopurine riboside, mercaptopurine, 5-fluorouracil, tegafur, doxifluridine, carmofur, cytarabine, cytarabine ocfosfate, enocitabine, S-1, gemcitabine, fludarabine, pemetrexed disodium and the like.

Used in the present description, the term "antitumor antibiotic" refers to an antibiotic with antitumor activity, and here "antibiotics" are produced by microorganisms and include substances that inhibit the growth or other functions of cells in organisms or other organisms. Examples of antitumor antibiotics include actinomycin D, doxorubicin, daunorubicin, neocarzinostatin, bleomycin, peplomycin, mitomycin C, aclarubicin, pirarubicin, epirubicin, zinostatin stimulater, idarubitsin, sirolimus, valrubicin and the like.

Used in the present description, the term "antineoplastic R is stiteler origin" includes compounds with antitumor activity, derived from plants, and those compounds that undergo chemical modification. Examples of anticancer agents of plant origin include vincristine, vinblastine, vindesine, etoposide, sobuzoxane, docetaxel, paclitaxel, vinorelbine and the like.

Used in the present description, the term "antitumor derivatives of camptothecin" includes camptothecin and refers to inhibitory compounds against proliferation of cancer cells that are structurally related to camptothecin. "Antitumor derivatives of camptothecin" is not specifically limited, but as an example, you can specify camptothecin, 10-hydroxycamptothecin, topotecan, irinotecan, 9-aminocamptothecin or the like. Irinotecan is metabolized in vivo and exhibits antitumor activity in the form of SN-38. It is believed that the derivatives of camptothecin have almost the same mechanism of action and activity as camptothecin (Nitta et al., cancer and chemotherapeutics, 14, 850-857 (1987), and so on).

Used in the present description, the term "anticancer complex platinum compounds" refers to complex platinum compounds with antitumor activity, and complex compounds of platinum" here refers to complex platinum compounds, which provide platinum to form the ion. Preferred examples of the platinum compounds include cisplatin, CIS-diamminedichloroplatinum(II)-ion; chloride chlorine(Diethylenetriamine)platinum(II); dichloro(Ethylenediamine)platinum(II)diamine(1,1-cyclobutanedicarboxylate)platinum(II)(carboplatin); spiroplatin; iproplatin; diammin(2-ethylmalonate)platinum(II); etilendiaminmonoatsetat(II) Aqua(1,2-diaminocyclohexane)selfadaptation(II); Aqua(1,2-diaminocyclohexane)melanoplinae(II); (1,2-diaminocyclohexane)melanoplinae(II); (4-carboxylat)(1,2-diaminocyclohexane)platinum(II); (1,2-diaminocyclohexane)(isocitrate)platinum(II); (1,2-diaminocyclohexane)occultopedia(II); ormaplatin; tetraploid; carboplatin; nedaplatin and oxaliplatin. In addition, other anticancer complex platinum compounds, illustrated in the present description generally known and are commercially available and/or can be obtained by specialists in this field, in accordance with conventional techniques.

Used in the present description, the term "antitumor inhibitors of tyrosine kinases" refers to inhibitors of tyrosine kinase with antitumor activity, and here the term "inhibitor of the tyrosine kinase" refers to a chemical substance for inhibiting the tyrosine kinase, which is involved in the transfer of γ-phosphate group of ATP to the hydroxyl group of a specific tyrosine in proteins. Examples of the antitumor inhibitors of tyrosine kinases include gefitinib, imatinib, erlotinib and the like.

Used in the present description, the term "monoclonal antibody" refers to an antibody obtained from a cell, forming a monoclonal antibody, and examples include cetuximab, bevacizumab, rituximab, alemtuzumab, trastuzumab and the like.

Used in the present description, the term "interferon" refers to interferon having anti-tumor activity, and in General in the case of viral infection is a glycoprotein having a molecular weight of about 20,000, which is produced/secreted from most animal cells. As well as, inhibiting the proliferation of viruses, interferon inhibits cell proliferation (in particular, tumor cells) and shows different types of immune effector activity, including enhancement of natural killer activity; and it is known as one of the cytokines. Examples of "interferon" include interferon α, interferon α-2A, interferon α-2b, interferon-β, interferon γ-1A, interferon γ-n1 and the like.

Used in the present description, the term "biological response modifiers" in the form of abbreviations presented as BRM and in General is a term specific to certain substances or drugs that lead to the achievement of individual favorable effects against tumors, details what the capabilities or other diseases through regulation of biological reactions, such as a protective mechanism available to the organisms, and the survival, proliferation or differentiation of tumor cells. Examples of "biological response modifiers" include baptisms, lentinan, sizofiran, picibanil, ubenimex and the like.

Used in the present description, the term "other antitumor agents" refers to the antitumor agent with antitumor activity, which is not included in any of the groups described above. Examples of "other anticancer agents" include mitoxantrone, L-asparaginase, procarbazine, dacarbazine, hydroxycarbamide, pentostatin, tretinoin, alefacept, darbepoietin Alfa, anastrozole, exemestane, bikalutamid, leiprorelina, flutamide, fulvestrant, pegaptanib of Octanate, denileukin diftitox, aldesleukin, thyrotropin alpha, arsenic trioxide, bortezomib, capecitabine, goserelin and the like.

All of the above "antitumor alkylating funds, antineoplastic antimetabolites", "antitumor antibiotics", "anticancer agents of plant origin", "antitumor complex compounds of platinum", "antitumor derivative camptothecin", "antitumor inhibitors of tyrosine kinases", "monoclonal antibodies, interferons, biological response modifiers and other p is tibooburra means" generally known and are commercially available or can be obtained by specialists in this field in accordance with the methods, known as such, or in accordance with well-known/used ways. Disclosed is a method of obtaining gefitinib, for example, in the description of U.S. patent No. 5770599; receive cetuximab, for example, in International publication WO96/40210; the method of obtaining bevacizumab, for example, in International publication WO94/10202; the method of obtaining oxaliplatin, for example, in the description of U.S. patent No. 5420319 and 5959133; the method of receiving gemcitabine, for example, in the description of U.S. patent No. 5434254 and 5223608; a method of producing camptothecin in the description of U.S. patent№№ 5162532, 5247089, 5191082, 5200524, 5243050 and 5321140; the method of receiving irinotecan, for example, in the description of U.S. patent No. 4604463; a method of producing topotecan, for example, in the description of U.S. patent No. 5734056; the method of obtaining temosolomida, for example, the description will not pass the examination, the Japan patent No. N4-5029; and a method of producing rituximab in the description will not pass the examination, the Japan patent No. H2 503143.

As an antitumor alkylating tools, such as the N-oxide nitrogen mustard, commercially available in the form of a product called "nitrogen", manufactured by Mitsubishi Pharma Corporation; cyclophosphamide commercially available under the product name Endoxan, manufactured by Shionogi & Co., Ltd.; ifosfamide commercially available under the product name Itemid, manufactured by Shionogi & Co., Ltd.; melphalan them which is sold under the product name alkeran, manufactured by GlaxoSmithKline; busulfan commercially available under the product name of Marlin, manufactured by Takeda pharmaceutical; mitobronitol commercially available under the product name Mabry, manufactured by Kyorin Pharmaceutical Co., Ltd; Carbogen commercially available under the product name athinon, manufactured by Sankyo & Co., Ltd.; thiotepa commercially available under the product name of esplin, manufactured by Sumitomo Pharmaceutical Co., Ltd; ranimustine commercially available under the product name of Temerin, manufactured by Mitsubishi Pharma Corporation; nimustine commercially available under the product name of Nigran, manufactured by Sankyo Co., Ltd.; temozolomide commercially available under the product name Temodal, manufactured by Schering-Plough Co., Ltd.; and carmustin commercially available under the product name gliadel, manufactured by Guilford Pharmaceuticals.

As antineoplastic antimetabolites, such as methotrexate commercially available under the product name methotrexate, manufactured by Takeda pharmaceutical; 6-mercaptopurine riboside commercially available under the product name thioinosine, manufactured by Aventis Co., Ltd.; mercaptopurine commercially available under the product name of leukeran, manufactured by Takeda pharmaceutical; 5-fluorouracil commercially available under the product name 5-FU, manufactured by Kyowa Hakko Co., Ltd.; tegafur is commercially available under the product name futraful, manufactured by Taiho Pharmaceutical Co., Ltd.; doxifluridine commercially available under the product name furtulon, manufactured by Roche Japan; carmofur commercially available under the product name Amateur, manufactured by Yamanouchi Pharmaceutical; cytarabine commercially available under the product name Ziloti, manufactured by Nippon Kayaku Co., Ltd.; cytarabine ocfosfate commercially available under the product name started, manufactured by Nippon Shinyaku Co., Ltd.; enocitabine commercially available under the product name sunrain, manufactured by Asahi Kasei Corporation; S-1 commercially available under the product name TS-1, manufactured by Taiho Pharmaceutical C0., Ltd.; gemcitabine commercially available under the product name Gemzar, manufactured by Eli Lily Co., Ltd.; fludarabine commercially available under the product name Fludara, manufactured by Japan Schering-Plough K.K.; and pemetrexed disodium commercially available under the product name of Kolya, manufactured by Eli Lily Co., Ltd.

As an antitumor antibiotics, such as actinomycin D commercially available under the product name Cosmegen, manufactured by Banyu Pharmaceutical Co., Ltd.; doxorubicin is commercially available under the product name Adriatic, manufactured by Kyowa Hakko Co., Ltd.; daunorubicin commercially available under the product name of daunomycin, manufactured by Meiji Seika co., Ltd.; neoka zinostatin commercially available under the product name neocarzinostatin, manufactured by Yamanouchi Pharmaceutical; bleomycin commercially available under the product name of bleo, manufactured by Nippon Kayaku Co., Ltd.; peplomycin commercially available under the product name peploe, manufactured by Nippon Kayaku Co., Ltd.; mitomycin With commercially available under the product name mitomycin, manufactured by Kyowa Hakko Co., Ltd.; aclarubicin commercially available under the product name of alazine, manufactured by Yamanouchi Pharmaceutical; pirarubicin commercially available under the product name pierobon, manufactured by Nippon Kayaku Co., Ltd.; epirubicin commercially available under the product name of farmorubicin manufactured by the company Pharmacia corporation; zinostatin stimulater commercially available under the product name of smancs, manufactured by Yamanouchi Pharmaceutical; idarubitsin commercially available under the product name idamycin manufactured by the company Pharmacia corporation; sirolimus commercially available under the product name of rapamune, manufactured by Wyeth; and valrubicin commercially available under the product name valstar, manufactured by Anthra pharmaceutical.

As anticancer agents of plant origin, for example, vincristine commercially available under the product name oncovin, manufactured by Shionogi & Co., Ltd.; vinblastine commercially available under the product name vinblastine produced by the company is Kyorin Pharmaceutical Co., Ltd,; vindesine commercially available under the product name filesin, manufactured by Shionogi & Co., Ltd.; etoposide commercially available under the product name of lastet, manufactured by Nippon Kayaku Co., Ltd.; sobuzoxane commercially available under the product name Parasolid, manufactured by Zenyaku Kogyo; docetaxel commercially available under the product name of the Taxotere, manufactured by Aventis Co., Ltd.; paclitaxel is commercially available under the product name Taxol, manufactured by Bristol-Myers K.K.; and vinorelbine commercially available under the product name navelbine, manufactured by Kyowa Hakko Co., Ltd.

As anticancer complex platinum compounds cisplatin commercially available under the product name Rand, manufactured by Nippon Kayaku Co., Ltd.; carboplatin commercially available under the product name of paraplatin, manufactured by Bristol-Myers K.K.; nedaplatin commercially available under the product name of acoupla, manufactured by Shionogi & Co., Ltd.; and oxaliplatin commercially available under the product name of Eloxatin, manufactured by Sanofi K.K.

As antitumoral derivatives camptothecin, for example, irinotecan commercially available under the product name campto, manufactured by Yakult Co., Ltd.; topotecan commercially available under the product name Hycamtin manufactured by GlaxoSmithKline;and camptothecin issued by the company Aldrich Chemical Company, U.S.A, etc.

As anticancer inhibitors of tyrosine kinases, such as gefitinib, commercially available under the product name of iressa, manufactured by AstraZeneca, imatinib commercially available under the product name Gleevec, manufactured by Novartis pharma K.K.; and erlotinib commercially available under the product name Tarceva manufactured by the company OSI pharmaceuticals, Inc.

As monoclonal antibodies, such as cetuximab commercially available under the product name Erbitux, manufactured by Bristol-Myers Squibb Company, bevacizumab commercially available under the product name Avastin, manufactured by Genentech Inc.; rituximab commercially available under the product name Rituxan, manufactured by Biogen Idec Inc.; alemtuzumab commercially available under the product name of campath, manufactured by Berlex, Inc.; and trastuzumab commercially available under the product name Herceptin, manufactured by Chugai Pharmaceutical Co., Ltd.;

As interferons, such as interferon α commercially available under the product name sumiferon, manufactured by Sumitomo Pharma Co., Ltd.; interferon α-2A commercially available under the product name chaperon-A, manufactured by Takeda pharmaceutical; interferon α-2b commercially available under the product name intron a, manufactured by Schering-Plough Co., Ltd.; interferon-β commercially available under the trade names the m product IFNβ, manufactured by Mochida Pharmaceutical Co., Ltd.; interferon γ-1A commercially available under the product name Immunomax-γ, manufactured by Shionogi & Co., Ltd.; and interferon γ-n1 commercially available under the product name of ogama, manufactured by Otsuka Pharmaceutical Co., Ltd.

As biological response modifiers, for example, christenings commercially available under the product name of the christening, manufactured by Sankyo Co., Ltd.; lentinan commercially available under the product name lentinan, manufactured by Aventis Co., Ltd.; sizofiran commercially available under the product name sonified, manufactured by Kaken Pharmaceuticals Co., Ltd.; picibanil commercially available under the product name picibanil, manufactured by Chugai Pharmaceuticals Co., Ltd.; and ubenimex commercially available under the product name bestatin, manufactured by Nippon Kayaku Co., Ltd.

As other anticancer agents, such as mitoxantrone commercially available under the product name Novantrone, manufactured by Wyeth-Lederie Japan; L-asparaginase commercially available under the product name lanasa, manufactured by Kyowa Hakko Co., Ltd.; procarbazine commercially available under the product name of natulan, manufactured by Roche Japan; dacarbazine commercially available under the product name dacarbazine, manufactured by Kyowa Hakko Co., Ltd.; hydroxycarbamide have to sell the same under the product name hydrea, manufactured by Bristol K.K.; pentostatin commercially available under the product name of kaporin produced by Chemo-Sero-Therapeutic Research Institute; tretinoin commercially available under the product name vesanoid, manufactured by Roche Japan; alefacept commercially available under the product name AMEVIVE, manufactured by Biogen Idec Inc.; darbepoietin alpha commercially available under the product name Aranesp, manufactured by Amgen Inc.; anastrozole commercially available under the product name arimidex, manufactured by AstraZeneca; exemestane commercially available under the product name Aromasin, manufactured by Pfizer Inc.; bikalutamid commercially available under the product name of casodex manufactured by AstraZeneca; leiprorelina commercially available under the product name lupulin, manufactured by Takeda Pharmaceutical; flutamide commercially available under the product name eulexin manufactured by Schering-Plough Co., Ltd.; fulvestrant commercially available under the product name faslodex, manufactured by AstraZeneca; pegaptanib of Octanate commercially available under the product name of macugen manufactured by the company Guilead Sciences, Inc.; denileukin diftitox commercially available under the product name touch of a button, manufactured by the company Ligand Pharmaceuticals Inc.; aldesleukin commercially available under the product name Proleukin, manufactured comp what their Chiron Corporation; thyrotropin alpha commercially available under the product name of thyrogen, manufactured by Genzyme, arsenic trioxide commercially available under the product name of trisenox manufactured by the company Cell Therapeutics, Inc.; bortezomib commercially available under the product name Velcade manufactured by the company Millenium; capecitabin commercially available under the product name xeloda manufactured by Roche; and goserelin commercially available under the product name Zoladex, manufactured by AstraZeneca.

Used in the present description, the term "antineoplastic agents" include antineoplastic agents selected from antineoplastic alkylating funds, antineoplastic antimetabolites", "antitumor antibiotics", "anticancer agents of plant origin", "antitumor complex compounds of platinum", "antitumor derivative camptothecin", "antitumor inhibitors of tyrosine kinases", "monoclonal antibodies, interferons, biological response modifiers and other anticancer agents".

Embodiments of the compounds represented by the above formula (I)will be described in more detail.

Each R1and R2that may be the same or different, represents a hydrogen atom; a halogen atom; a group of the lower alkyl, the which may be substituted by 1-3 fluorine atoms; or cyclopropyl group.

R1preferably represents the group of lower alkyl having 1-2 carbon atoms which may be substituted by 1-3 fluorine atoms; cyclopropyl group; or a chlorine atom.

R1preferably represents methyl group, ethyl group, deformational group, triptorelin group, cyclopropyl group or a chlorine atom;

R1more preferably represents ethyl group, deformational group, triptorelin group, cyclopropyl group or a chlorine atom;

R2preferably represents a hydrogen atom.

For R3and R4one of R3and R4represents a hydrogen atom, and the other of R3and R4is:

(a) the group of lower alkyl, substituted NRaRbwhere each Raand Rbthat may be the same or different, represent a hydrogen atom, a group of lower alkyl, benzyl group or cycloalkyl group having 3-6 carbon atoms, where cycloalkyl group may be substituted by one or more substituents, which may be the same or different, selected from the following compounds PP. 1-3:

1) the group of lower alkyl;

2) Deputy selected from <group Deputy β>; and

3) the group of lower alkyl, substituted by one or more substituents, in the swear of < group Deputy β>; and cycloalkyl group may include an unsaturated bond;

b) 4-6-membered aliphatic heterocyclic group selected from azetidine group, pyrrolidinyl group, piperidinyl group and piperazinilnom group; or

c) the group of lower alkyl, substituted 4-6-membered aliphatic heterocyclic group selected from azetidine group, pyrrolidinyl group, piperidinyl group and piperazinilnom group;

d) 5 - or 6-membered aromatic heterocyclic group selected from pyrrolidino group, imidazolidine group, pyrazolidine group, peredelnoj group, personalni group and pyrimidinyl group; or

e) the group of lower alkyl, substituted 5 - or 6-membered aromatic heterocyclic group selected from pyrrolidino group, imidazolidine group, pyrazolidine group, peredelnoj group, personalni group and pyrimidinyl group, where each of the aliphatic heterocyclic group and aromatic heterocyclic group independently may be substituted by one or more substituents, which may be the same or different, selected from the following compounds PP. 1-4:

1) the group of lower alkyl;

2) Deputy selected from <group Deputy β>;

3) the group of lower alkyl, substituted onemile more substituents, selected from <group Deputy β>; and

4) cycloalkyl group having 3-6 carbon atoms that may be substituted by one or more substituents selected from <group Deputy β>;

For R3and R4, preferably, one of R3and R4represented a hydrogen atom and the other of R3and R4was:

(a) the group of lower alkyl, substituted NRaRbwhere each Raand Rbthat may be the same or different, represent a hydrogen atom, a group of lower alkyl, or cycloalkyl group having 5-6 carbon atoms, where cycloalkyl group may be substituted by one or more substituents, which may be the same or different, selected from the following compounds PP. 1-3:

1) the group of lower alkyl;

2) Deputy selected from <group Deputy β>; and

3) the group of lower alkyl, substituted by one or more substituents selected from <group Deputy β>or

b) 4-6-membered aliphatic heterocyclic group selected from azetidine group, pyrrolidinyl group, piperidinyl group, aliphatic heterocyclic group may be substituted by one or more substituents, which may be the same Lili different, selected from the following compounds PP. 1-3:

1) group the and lower alkyl;

2) Deputy selected from <group Deputy β>; and

3) the group of lower alkyl, substituted by one or more substituents selected from <group Deputy β>.

<Group Deputy β> R3and R4preferably represents the group consisting of halogen atom, hydroxy-group, amino group, groups, lower alkylsulfonyl groups and lower alkoxy.

For R3and R4preferably, one of R3and R4represented a hydrogen atom and the other of R3and R4represented group, amino lower alkyl (where specified lower alkyl represents a linear or branched alkyl group having 1-3 carbon atoms, which is N-substituted or N,N-di-substituted linear or branched alkyl group having 1-5 carbon atoms; piperidinyl group, which is N-substituted linear or branched alkyl group having 1-5 carbon atoms; pyrrolidinyloxy group, which is N-substituted linear or branched alkyl group having 1-5 carbon atoms; azetidinol group, which is N-substituted linear or branched alkyl group having 1-5 carbon atoms; or cycloalkyl group having 5-6 carbon atoms, where each of piperidinyloxy group, pyrrolidinyl group and azetidinone group independently can be, in addition to the, substituted linear or branched alkyl group having 1-3 carbon atoms, and cycloalkyl group may be substituted linear or branched alkyl group having 1-3 carbon atoms, optionally having a hydroxy-group. Here piperidinyl group is preferably N-substituted piperidine-3-yl, N-substituted piperidine-4-yl, or the like. Pyrrolidinyl group is preferably N-substituted pyrrolidin-2-yl, N-substituted pyrrolidin-3-yl, or the like, and preferably N-substituted pyrrolidin-2-yl. Azetidinone group is preferably N-substituted, azetidin-3-yl or the like. Cycloalkyl group is preferably cyclopentyl, cyclohexyl or the like, is preferable, cyclopentyl.

For R3and R4still preferably, one of R3and R4represented a hydrogen atom and the other of R3and R4represented a linear or branched alkyl group having 1-3 carbon atoms, which is substituted by dimethylaminopropoxy, isopropylaminocarbonyl, 1,1-dimethylpropyleneurea or 1-butylamino; piperidinyloxy group, which is N-substituted linear or branched alkyl group having 1-5 carbon atoms; pyrrolidinyloxy group, which is N-substituted linear or branched alkyl the Noah group, 1-5 carbon atoms; azetidinol group, which is N-substituted linear or branched alkyl group having 1-5 carbon atoms; or cyclopentyloxy group which may be substituted by a methyl group or hydroxymethylene group, where piperidinyl group, pyrrolidinyl group and azetidinone group may be additionally substituted linear or branched alkyl group having 1-3 carbon atom.

R5represents a hydrogen atom, a cyano, a halogen atom or a group of the lower alkyl.

R5represents preferably a hydrogen atom, a cyano, a halogen atom or methyl group, preferably, a cyano, a halogen atom or methyl group, particularly preferably a cyano, fluorine atom or methyl group.

For R1-R5from the point of view of the effect of inhibition of cell proliferation on the basis of the effect of PLK1 inhibition, preferred the following case (A), preferably the following case (I), and preferable to, the following case (S).

(A) Case,

where R1represents the group of lower alkyl having 1-2 carbon atoms which may be substituted by 1-3 fluorine atoms, cyclopropene group or a halogen atom;

R2represents a hydrogen atom;

one of R3and R4is Alamogordo, while the other of R3and R4represents a group of the amino lower alkyl (where specified lower alkyl represents a linear or branched alkyl group having 1-3 carbon atoms, which is N-substituted or N,N-di-substituted linear or branched alkyl group having 1-5 carbon atoms; piperidinyl group, which is N-substituted linear or branched alkyl group having 1-5 carbon atoms; pyrrolidinyloxy group, which is N-substituted linear or branched alkyl group having 1-5 carbon atoms; azetidinol group, which is N-substituted linear or branched alkyl group having 1-5 carbon atoms; or cycloalkyl group having 5-6 carbon atoms, where each of piperidinyloxy group, pyrrolidinyl group and azetidinone group independently may also be substituted linear or branched alkyl group having 1-3 carbon atoms, and cycloalkyl group may be substituted linear or branched alkyl group having 1-3 carbon atoms, optionally having a hydroxy-group; and

R5represents a cyano, a halogen atom or methyl group.

(C) Case,

where R1represents methyl group, ethyl group, deformational group, triptorelin group, cyclopropyl group or the volume of chlorine;

R2represents a hydrogen atom;

one of R3and R4represents a hydrogen atom while the other of R3and R4represents a linear or branched alkyl group having 1-3 carbon atoms, which is substituted by dimethylaminopropoxy, isopropylaminocarbonyl, 1,1-dimethylpropyleneurea, or tert-butylamino; piperidinyloxy group, which is N-substituted linear or branched alkyl group having 1-5 carbon atoms; pyrrolidinyloxy group, which is N-substituted linear or branched alkyl group having 1-5 carbon atoms; azetidinol group, which is N-substituted linear or branched alkyl group having 1-5 carbon atoms; or cyclopentyloxy group which may be substituted by a methyl group or hydroxymethylene group, where each group piperidinyloxy, pyrrolidinyloxy group and azetidinone group independently may in addition be substituted linear or branched alkyl group having 1-3 carbon atoms; and

R5represents cyano, fluorine atom or methyl group.

(C) Case,

where R1represents ethyl group, deformational group, triptorelin group, cyclopropyl group or a chlorine atom;

R2represents a hydrogen atom;

one of R3and R4represents a hydrogen atom, while the other of R3and R4represents tert-butylaminoethyl group; 1-methyldiethanolamine group; piperidine-3-strong group, which is N-substituted linear or branched alkyl group having 1-5 carbon atoms; piperidine-4-strong group, which is N-substituted linear or branched alkyl group having 1-5 carbon atoms; pyrrolidin-2-strong group, which is N-substituted linear or branched alkyl group having 1-5 carbon atoms; azetidin-3-strong group, which is N-substituted linear or branched alkyl group having 1-5 carbon atoms; or cyclopentyloxy group which may be substituted by a methyl group or hydroxymethylene group, where the piperidine-3-ilen group, piperidine-4-ilen group, pyrrolidin-2-ilen group, azetidin-3-ilen group may be additionally substituted by a methyl group; and

R5represents a cyano or fluorine atom.

<Group Deputy β> represents the group consisting of halogen atom, hydroxy-group, nitro group, ceanography, amino, carbamoyl group, aminosulfonyl group, aminogroup, groups, lower alkylsulfonyl, groups, lower alkylsulfonyl, groups, lower alkoxy groups of the lower alkoxycarbonyl, groups, lower alkoxycarbonyl, groups, lower Alka is Oila, group lower alkanoyloxy, groups, lower alkylthio, carboxyl group and benzyl group.

<Group Deputy β> represents preferably a group consisting of a halogen atom, hydroxy-group, amino group, groups, lower alkylsulfonyl groups and lower alkoxy.

In connection with this arrow asymmetric carbon atom in the following substructure, the compound represented by formula (I)is preferably an S-shape.

The compound of the above formula (I) is preferably

(a) 2-[((1S)-1-{4-[2-(tert-butylamino)-1-hydroxyethyl]phenyl}ethyl)amino]-4-(8-ethylimidazole[1,2-a]pyridine-3-yl)pyrimidine-5-carbonitrile (examples 2 and 3);

(b) 4-(8-ethylimidazole[1,2-a]pyridine-3-yl)-2-[((1S)-1-{4-[hydroxy(1-isopropylpiperazine-4-yl)methyl]phenyl}ethyl)amino] pyrimidine-5-carbonitrile (examples 9 and 10);

(c) 4-(8-cyclopropylamino[1,2-a]pyridine-3-yl)-2-[((1S)-1-{4-[hydroxy(1-methylpiperidin-4-yl)methyl]phenyl}ethyl)amino] pyrimidine-5-carbonitrile (example 12);

(d) 4-(8-ethylimidazole[1,2-a]pyridine-3-yl)-2-[((1S)-1-{4-[hydroxy(1-methylpiperidin-3-yl)methyl]phenyl}ethyl)amino]pyrimidine-5-carbonitrile (examples 13, 14, 15 and 16);

(e) 2-[((1S)-1-{4-[2-(tert-butylamino)-1-hydroxyethyl]phenyl}ethyl)amino]-4-(8-chloroimidazo[1,2-a]pyridine-3-yl)pyrimidine-5-carbonitrile (example 22);

(f) 2-[((1S)-1-{4-[2-(tert-butylamino)-1-hydroxyethyl]phenyl}ethyl)amino]--[8-deformity)imidazo[1,2-a]pyridine-3-yl)pyrimidine-5-carbonitrile (examples 4 and 21);

(g) 4-(8-cyclopropylamino[1,2-a]pyridine-3-yl)-2-[((1S)-1-{4-[(1,2-dimethylpyridin-2-yl)(hydroxy)methyl]phenyl}ethyl)amino]pyrimidine-5-carbonitrile (examples 23, 24, 25 and 26);

(h) (1S)-2-(tert-butylamino)-1-[4-((1S)-1-{[4-(8-chloroimidazo[1,2-a]pyridine-3-yl)-5-ftorpirimidinu-2-yl]amino}ethyl)phenyl]ethanol (example 27);

(i) (1S)-1-[4-((1S)-1-{[4-(8-chloroimidazo[1,2-a]pyridine-3-yl)-5-ftorpirimidinu-2-yl]amino}ethyl)phenyl]-2-[(1-methylcyclopentene) amino]ethanol (example 28);

(j) (1S)-2-(tert-butylamino)-1-[4-((1S)-1-{[4-(8-cyclopropylamino[1,2-a]pyridine-3-yl)-5-methylpyrimidin-2-yl]amino}ethyl)phenyl]ethanol (example 29);

(k) (1S)-2-(tert-butylamino)-1-[4-((1S)-1-{[4-(8-cyclopropylamino[1,2-a]pyridine-3-yl)-5-coorperation-2-yl]amino}ethyl)phenyl]ethanol (example 30);

(l) (1S)-2-(tert-butylamino)-1-{4-[(1S)-1-({5-fluoro-4-[8-(trifluoromethyl)imidazo[1,2-a]pyridine-3-yl]pyrimidine-2-yl}amino)ethyl]phenyl}ethanol (example 31);

(m) [4-((1S)-1-{[4-(8-chloroimidazo[1,2-a]pyridine-3-yl)-5-ftorpirimidinu-2-yl]amino}ethyl)phenyl](1,2-dimethylpyridin-2-yl)methanol (examples 32 and 33);

(n) 1-[4-((1S)-1-{[4-(8-chloroimidazo[1,2-a]pyridine-3-yl)-5-ftorpirimidinu-2-yl]amino}ethyl)phenyl]-2-(dimethylamino)-2-methylpropan-1-ol (examples 34 and 35);

(o) [4-((1S)-1-{[4-(8-chloroimidazo[1,2-a]pyridine-3-yl)-5-ftorpirimidinu-2-yl]amino}ethyl)phenyl](1-isopropylpyridine-3-yl)methanol (examples 36 and 37); or

(p) (1S)-2-(tert-butylamino)-1-{4-[(1S)-1-({4-(8-deformity)imidazo[1,2-a]pyridine-3-yl]-5-ftorpirimidinu-2-yl}amino)ethyl]phenyl}etano is (example 38),

or their pharmaceutically acceptable salt or ester.

In addition, the preferred aspects of the present invention can also be represented as follows.

(1) the Compound of the above formula (I) or its pharmaceutically acceptable salt or ester in which R5represents a hydrogen atom, a cyano, a halogen atom or a methyl group; or

(2) the Compound of the above formula (I) or its pharmaceutically acceptable salt or ester in which R1represents the group of lower alkyl having one or two carbon atoms that may be substituted by 1-3 fluorine atoms; cyclopropyl group; or a chlorine atom, and R2represents a hydrogen atom; or

(3) the Compound described above in paragraph(1) or (2) or its pharmaceutically acceptable salt or ester, in which <substituent β> represents a halogen atom, a hydroxy-group, amino group, lower alkylsulfonyl group and a lower alkoxy; or

(4) the Compound described in any of paragraphs.(1)to(3), or its pharmaceutically acceptable salt or ester in which one of R3and R4represents a hydrogen atom, and the other of R3and R4is:

(a) the group of lower alkyl, substituted NRaRbwhere each of Raand Rbthat may be the same or the difference is significant, represents a hydrogen atom, a group of lower alkyl, or cycloalkyl group having 5-6 carbon atoms, where cycloalkyl group may be substituted by one or more substituents, which may be the same or different, and selected from the following paragraphs. 1)-3):

1) the group of lower alkyl;

2) a substituent selected from <group Deputy β>; and

3) the group of lower alkyl, substituted by one or more substituents selected from <group Deputy β>or

b) 4-6-membered aliphatic heterocyclic group selected from azetidine group, pyrrolidinyl group and piperidinyloxy group, aliphatic heterocyclic group may be substituted by one or more substituents, which may be the same or different, selected from the following paragraphs. 1-4:

1) the group of lower alkyl;

2) a substituent selected from <group Deputy β>; and

3) the group of lower alkyl, substituted by one or more substituents selected from <group Deputy β>or

(5) the Compound described in any of the above paragraphs. (1)to(4), or its pharmaceutically acceptable salt or ester, in which:

R1represents the group of lower alkyl having one or two carbon atoms that may be substituted by 1-3 fluorine atoms; cyclopropyl group; or a halogen atom;

R 2represents a hydrogen atom;

one of R3and R4represents a halogen atom, while the other of R3and R4represents an amino lower alkyl (where specified lower alkyl represents a linear or branched alkyl group having 1-3 carbon atoms, which is N-substituted or N,N-di-substituted linear or branched alkyl group having 1-5 carbon atoms; piperidinyl group, which is N-substituted linear or branched alkyl group having 1-5 carbon atoms; pyrrolidinyloxy group, which is N-substituted linear or branched alkyl group having 1-5 carbon atoms; azetidinone group, which is N-substituted linear or branched alkyl group having 1-5 carbon atoms; or cycloalkyl group having 5-6 carbon atoms, where each of piperidine group, pyrrolidinyl group and azetidinone group may be additionally substituted linear or branched alkyl group having 1-3 carbon atoms, and cycloalkyl group may be substituted linear or branched alkyl group having 1-3 carbon atoms, optionally having a hydroxy-group; and

R5represents a cyano, a halogen atom or a methyl group; or

(6) the Compound described in any of the above paragraphs. (1)to(5), or the th pharmaceutically acceptable salt or ester, where:

R1represents methyl group, ethyl group, deformational group, triptorelin group, cyclopropyl group or a chlorine atom;

R2represents a hydrogen atom;

one of R3and R4represents a hydrogen atom while the other of R3and R4represents a linear or branched alkyl group having 1-3 carbon atoms, which is substituted by dimethylaminopropoxy, isopropylaminocarbonyl, 1,1-dimethylpropyleneurea or tert-butylamino; pyridinyl group that N-substituted linear or branched alkyl group having 1-5 carbon atoms; pyrrolidinyloxy group, which is N-substituted linear or branched alkyl group having 1-5 carbon atoms; azetidinol group, which is N-substituted linear or branched alkyl group having 1-5 carbon atoms; or cycloalkyl group which may be substituted by a methyl group or hydroxymethylene group, where each group piperidines, pyrrolidinyloxy group and azetidinone group independently can be, additionally, a substituted linear or branched alkyl group having 1-3 carbon atoms; and

R5represents cyano, fluorine atom or methyl group.

For the combined drug in accordance with the image is the group of which is formed of two separate preparations, it is preferable that one or both of two separate drugs was/were oral medication (drugs) or parenteral drugs (drugs).

In the combined preparation according to the invention, which is formed of two separate preparations, preferably one drug, together with a pharmaceutically acceptable carrier or diluent, was represented by a formula containing:

(a) 2-[((1S)-1-{4-[2-(tert-butylamino)-1-hydroxyethyl]phenyl}ethyl)amino]-4-(8-ethylimidazole[1,2-a]pyridine-3-yl)pyrimidine-5-carbonitrile;

(b) 4-(8-ethylimidazole[1,2-a]pyridine-3-yl)-2-[((1S)-1-{4-[hydroxy(1-isopropylpiperazine-4-yl)methyl]phenyl}ethyl)amino] pyrimidine-5-carbonitrile;

(c) 4-(8-cyclopropylamino[1,2-a]pyridine-3-yl)-2-[((1S)-1-{4-[hydroxy(1-methylpiperidin-4-yl)methyl]phenyl}ethyl)amino] pyrimidine-5-carbonitrile;

(d) 4-(8-ethylimidazole[1,2-a]pyridine-3-yl)-2-[((1S)-1-{4-[hydroxy(1-methylpiperidin-3-yl)methyl]phenyl}ethyl)amino]pyrimidine-5-carbonitrile;

(e) 2-[((1S)-1-{4-[2-(tert-butylamino)-1-hydroxyethyl]phenyl}ethyl)amino]-4-(8-chloroimidazo[1,2-a]pyridine-3-yl)pyrimidine-5-carbonitrile;

(f) 2-[((1S)-1-{4-[2-(tert-butylamino)-1-hydroxyethyl]phenyl}ethyl)amino]-4-[8-deformity)imidazo[1,2-a]pyridine-3-yl)pyrimidine-5-carbonitrile;

(g) 4-(8-cyclopropylamino[1,2-a]pyridine-3-yl)-2-[((1S)-1-{4-[(1,2-dimethylpyridin-2-yl)(hydroxy)methyl] - dryer is l}ethyl)amino]pyrimidine-5-carbonitrile;

(h) (1S)-2-(tert-butylamino)-1-[4-((1S)-1-{[4-(8-chloroimidazo[1,2-a]pyridine-3-yl)-5-ftorpirimidinu-2-yl]amino}ethyl)phenyl]ethanol;

(i) (1S)-1-[4-((1S)-1-{[4-(8-chloroimidazo[1,2-a]pyridine-3-yl)-5-ftorpirimidinu-2-yl]amino}ethyl)phenyl]-2-[(Methylcyclopentane) amino]ethanol;

(j) (1S)-2-(tert-butylamino)-1-[4-((1S)-1-{[4-(8-cyclopropylamino[1,2-a]pyridine-3-yl)-5-methylpyrimidin-2-yl]amino}ethyl)phenyl]ethanol;

(k) (1S)-2-(tert-butylamino)-1-[4-((1S)-1-{[4-(8-cyclopropylamino[1,2-a]pyridine-3-yl)-5-coorperation-2-yl]amino}ethyl)phenyl]ethanol;

(l) (1S)-2-(tert-butylamino)-1-{4-[(1S)-1-({5-fluoro-4-[8-(trifluoromethyl)imidazo[1,2-a]pyridine-3-yl]pyrimidine-2-yl}amino)ethyl]phenyl}ethanol;

(m) [4-((1S)-1-{[4-(8-chloroimidazo[1,2-a]pyridine-3-yl)-5-ftorpirimidinu-2-yl]amino}ethyl)phenyl](1,2-dimethylpyridin-2-yl)methanol;

(n) 1-[4-((1S)-1-{[4-(8-chloroimidazo[1,2-a]pyridine-3-yl)-5-ftorpirimidinu-2-yl]amino}ethyl)phenyl]-2-(dimethylamino)-2-methylpropan-1-ol;

(o) [4-((1S)-1-{[4-(8-chloroimidazo[1,2-a]pyridine-3-yl)-5-ftorpirimidinu-2-yl]amino}ethyl)phenyl](1-isopropylpyridine-3-yl)methanol; or

(p) (1S)-2-(tert-butylamino)-1-{4-[(1S)-1-({4-(8-deformity)imidazo[1,2-a]pyridine-3-yl]-5-ftorpirimidinu-2-yl}amino)ethyl]phenyl}ethanol

or their pharmaceutically acceptable salt or ester.

Combined preparation according to the invention, which contains two separate drug can also be combined, with at least one drug, enabling the m together with a pharmaceutically acceptable carrier or diluent antitumor agent, selected from the group consisting of antitumor alkylating funds, antitumor antimetabolites, antitumor antibiotics, anticancer agents of plant origin, antitumor of platinum complex compounds, antitumor derivative camptothecin, antitumor of inhibitron tyrosine kinases, monoclonal antibodies, interferons, biological response modifiers, and other anticancer agents (in this description, the definition of each antitumor agents has the same meaning as defined above), or their pharmaceutically acceptable salt, or a complex ester.

The pharmaceutical composition in accordance with the invention preferably includes, together with a pharmaceutically acceptable carrier or diluent,

(a) 2-[((1S)-1-{4-[2-(tert-butylamino)-1-hydroxyethyl]phenyl}ethyl)amino]-4-(8-ethylimidazole[1,2-a]pyridine-3-yl)pyrimidine-5-carbonitrile;

(b) 4-(8-ethylimidazole[1,2-a]pyridine-3-yl)-2-[((1S)-1-{4-[hydroxy(1-isopropylpiperazine-4-yl)methyl]phenyl}ethyl)amino] pyrimidine-5-carbonitrile;

(c) 4-(8-cyclopropylamino[1,2-a]pyridine-3-yl)-2-[((1S)-1-{4-[hydroxy(1-methylpiperidin-4-yl)methyl]phenyl}ethyl)amino] pyrimidine-5-carbonitrile;

(d) 4-(8-ethylimidazole[1,2-a]pyridine-3-yl)-2-[((1S)-1-{4-[hydroxy(1-methylpiperidin-3-yl)methyl]phenyl}ethyl)amino]pyrimidine-5-carbonitrile;

(e) 2-[((1S)-1-{4-[2-tert-butylamino)-1-hydroxyethyl]phenyl}ethyl)amino]-4-(8-chloroimidazo[1,2-a]pyridine-3-yl)pyrimidine-5-carbonitrile;

(f) 2-[((1S)-1-{4-[2-(tert-butylamino)-1-hydroxyethyl]phenyl}ethyl)amino]-4-[8-deformity)imidazo[1,2-a]pyridine-3-yl)pyrimidine-5-carbonitrile;

(g) 4-(8-cyclopropylamino[1,2-a]pyridine-3-yl)-2-[((1S)-1-{4-[(1,2-dimethylpyridin-2-yl)(hydroxy)methyl]phenyl}ethyl)amino]pyrimidine-5-carbonitrile ;

(h) (1S)-2-(tert-butylamino)-1-[4-((1S)-1-{[4-(8-chloroimidazo[1,2-a]pyridine-3-yl)-5-ftorpirimidinu-2-yl]amino}ethyl)phenyl]ethanol;

(i) (1S)-1-[4-((1S)-1-{[4-(8-chloroimidazo[1,2-a]pyridine-3-yl)-5-ftorpirimidinu-2-yl]amino}ethyl)phenyl]-2-[(1-methylcyclopentene) amino]ethanol;

(j) (1S)-2-(tert-butylamino)-1-[4-((1S)-1-{[4-(8-cyclopropylamino[1,2-a]pyridine-3-yl)-5-methylpyrimidin-2-yl]amino}ethyl)phenyl]ethanol;

(k) (1S)-2-(tert-butylamino)-1-[4-((1S)-1-{[4-(8-cyclopropylamino[1,2-a]pyridine-3-yl)-5-coorperation-2-yl]amino}ethyl)phenyl]ethanol;

(l) (1S)-2-(tert-butylamino)-1-{4-[(1S)-1-({5-fluoro-4-[8-(trifluoromethyl)imidazo[1,2-a]pyridine-3-yl]pyrimidine-2-yl}amino)ethyl]phenyl}ethanol;

(m) [4-((1S)-1-{[4-(8-chloroimidazo[1,2-a]pyridine-3-yl)-5-ftorpirimidinu-2-yl]amino}ethyl)phenyl](1,2-dimethylpyridin-2-yl)methanol;

(n) 1-[4-((1S)-1-{[4-(8-chloroimidazo[1,2-a]pyridine-3-yl)-5-ftorpirimidinu-2-yl]amino}ethyl)phenyl]-2-(dimethylamino)-2-methylpropan-1-ol;

(o) [4-((1S)-1-{[4-(8-chloroimidazo[1,2-a]pyridine-3-yl)-5-ftorpirimidinu-2-yl]amino}ethyl)phenyl](1-isopropylpyridine-3-yl)methanol; or

(p) (1S)-2-(tert-butylamino)-1-{4-[(1S)-1-({4-(8-deformity)imidazo[1,2-a]pyridine-3-yl]-5-ftorpirimidinu-2-yl}AMI is about)ethyl]phenyl}ethanol

or their pharmaceutically acceptable salt or ester.

Next will be described a representative methods for obtaining compounds of the present invention.

Scheme 1A: the Method of obtaining the compounds of formula (I) from compounds of formula (IIa)

Scheme 1A

The compound of formula (I) in accordance with the invention (where R1, R2, R3, R4and R5are the same as described above) can be synthesized, exposing first the compound of formula (IIa) (where R1, R2, R3, R4and R5are the same as described above) of the oxidation reaction to obtain compounds of formula (IIIa) (where R1, R2and R5are the same as described above, and n=1 or 2), and then perform the substitution reaction between the compound of formula (IIIa), phenethylamine above formula IV (where R3and R4are the same as described above).

The compound of formula (IIIa) can be synthesized by oxidation of compounds of formula (IIa) in a solvent such as dichloromethane, chloroform, N,N-dimethylformamide, or the like, using an oxidizing agent such as m-chloroperbenzoic acid (m-CPBA), benzoylperoxide, a solution of hydrogen peroxide periodate sodium or the like, preferably, using m-chloroperbenzoic acid. In this reactions is, m-chloroperbenzoic acid (m-CPBA) is used in amounts of 2-5 moles, preferably 2 moles, to 1 pray the compounds of formula (IIa). The reaction temperature can be appropriately selected by experts in the field, in accordance with the starting compound or reaction solvent, but the reaction temperature is usually from 0 ° C to room temperature. The reaction is usually completed within 1 to 24 hours, but the duration of the reaction may be appropriately increased or decreased. Furthermore, the obtained compound of the above formula (IIIa) may be subjected to the next reaction without separation and purification.

The substitution reaction between the compound of the above formula (IIIa) and phenethylamines the above formula (IV) is preferably carried out in the presence of a base (for example, inorganic bases such as potassium carbonate and sodium bicarbonate, or organic bases such as triethylamine and diisopropylethylamine). The reaction solvent for use include chloroform, tetrahydrofuran, N,N-dimethylformamide, dimethylsulfoxide and the like, and preferably includes chloroform and tetrahydrofuran. In this reaction, phenetylamine the above formula (IV) is used in an amount of from 0.5 to 3 moles, to 1 pray compounds represented by formula (IIIa). Temperatures the reaction may be appropriately selected by experts in the field in accordance with the starting compound or reaction solvent, but the reaction temperature is usually from room temperature to the boiling point of the solvent is preferably used at room temperature. The reaction is usually completed within 1 to 24 hours, but the duration of the reaction may be appropriately increased or decreased.

Scheme 1b: the Method of obtaining the compounds of formula (I) from compounds of formula (IIb)

Scheme 1b

The compound of formula (I) in accordance with the invention (where R1, R2, R3, R4and R5are the same as described above) can be synthesized by conducting a substitution reaction between the compound of formula (IIa) (where R1, R2and R5represent the same as defined above) and phenethylamine represented by the above formula (IV) (where R3and R4represent the same as defined above).

The substitution reaction between the compound of the above formula (IIb) and phenethylamines the above formula (IV) is preferably carried out in the presence of a base (for example, inorganic bases such as potassium carbonate and sodium carbonate, sodium cesium and sodium bicarbonate, or organic bases such as triethylamine and diisopropylethylamine). The reaction solvent for use include chloroform, tetrahydrofuran, N,N-dimethylformamide, N,N-dimetil teamid, N-methyl-2-pyrrolidinone, dimethylsulfoxide and the like, and preferably includes N,N-dimethylformamide, N,N-dimethylacetamide, N-methyl-2-pyrrolidinone. In this reaction, phenetylamine the above formula (IV) is used in an amount of from 0.5 to 3 moles, to 1 pray compounds represented by formula (IIb). The reaction temperature can be appropriately selected by experts in the field, in accordance with the starting compound or reaction solvent, but the reaction temperature is usually from room temperature to the boiling point of the solvent, preferably from 80 up to 200ºC. The reaction is usually completed within 1 to 24 hours, but the duration of the reaction may be appropriately increased or decreased.

Diagram 2A: Representative method for obtaining compounds of formula (IIa)

Scheme 2A

The compound represented by the above formula (VIa), (where R5is the same as defined above) can be synthesized by the reaction of the compound Still between CIS-1-ethoxy-2-tri-n-batilolum (which may be synthesized in accordance with the method described in document J. Am. Chem. Soc., 1977, 99, 7365) and the compound represented by the above formula (Va) (where R5is the same as defined above), using dichlorobis(triphenylphosphine)palladium (II) in the quality of the ve catalyst. The reaction solvent is preferably acetonitrile, and the reaction temperature is usually from room temperature to the boiling point of the solvent, and preferably, the boiling point of the solvent. The reaction is usually completed within 1 to 24 hours, but the duration of the reaction may be appropriately increased or decreased.

The compound represented by the above formula (VIIa) (where R5is the same as defined above) can be obtained by the interaction of the compounds represented by the above formula (VIa) with N-bromosuccinimide in 1,4-dioxane. When this reaction is used 1-3 mol, preferably 1 mol of N-bromosuccinimide to 1 pray the compounds of formula (VIa). The reaction temperature can be appropriately selected by experts in the field, in accordance with the starting compound, but the reaction temperature is usually from 0 ° C to room temperature. The reaction is usually completed within 1 to 12 hours, but the duration of the reaction may be appropriately increased or decreased. The compound obtained of the formula (VIIa) may be subjected to the subsequent reaction without further isolation and purification.

The compound represented by the above formula (IIa) (where R1, R2and R5represent the same as defined above) can be synthesized from the compound, not only at the authorized above formula (VIIa) and compounds represented by the above formula (VIII) (where R 1and R2represent the same as defined above) in 1,4-dioxane. When this reaction is used 1-3 mol, preferably 1 mol of the compound represented by the above formula (VIII) to 1 pray the compounds of formula (VIIa). The reaction temperature can be appropriately selected by experts in the field, in accordance with the starting compound, but the reaction temperature is usually from room temperature to the boiling point of the solvent, preferably from room temperature to 50'C. The reaction is usually completed within 1 to 24 hours, but the duration of the reaction may be appropriately increased or decreased.

The compound represented by the above formula (Va), for example, is 4-chloro-2-(methylsulfanyl)-5-pyrimidinecarbonitrile, or the like, and a compound represented by the above formula (VIII)represents, for example, 2-amino-3-picoline, or similar connection. These compounds or are commercially available or can be synthesized from the output connection method, generally known to experts in the field, or an equivalent method (literature: international publication WO2004/043936, pages 32-33 and so on).

Scheme 2b: Representative method for obtaining compounds of formula (IIb)

Scheme 2b

The compound of the above formula (IIb) (where R , R2and R5represent the same as defined above) can be synthesized using the same method, as shown in figure 2A, of the compounds represented by the above formula (Vb) (where R5is as defined above) as a starting material instead of the compound represented by the above formula (Va) in figure 2A; see figure 2b.

The compound represented by the above formula (Vb)represents, for example, 2,4-dichloro-5-methylpiperid and the like, and a compound represented by the above formula (VIII)represents, for example, 2-aminopyralid and others like him, who are both or are commercially available or can be synthesized from commercially available compounds by a method generally known to experts in the field, or an equivalent method (literature: international publication WO2004/043936, pages 32-33 and so on).

Figure 3: Representative method for obtaining compounds of formula (IV)

Scheme 3

The compound of the above formula (IX) (where Boc is tert-butoxycarbonyl group) can be synthesized using commercially available (S)-(-)-1-(4-bromophenyl)ethylamine (the above compound (VIII)), in accordance with the method, generally known to experts in this field (Literature: Protective Groups in Organic Synthesis, the third edition, written by T.W. Greene, John Wiley & Sons Publication, page 518-524, etc.).

Then the compound of the above formula (XI) (where Boc, R3and R4represent the same as defined above) can be synthesized by first subjecting n-utillity the effects of compounds of the above formula (IX) in tetrahydrofuran to obtain argillite as the intermediate reaction, and then the interaction with the ketone of the above formula (Xa) (where R3and R4represent the same as defined above) or an aldehyde of the above formula (Xb), (where R4represent the same as defined above), which are both electrophile. When the interaction is 2-5 mol, preferably 2 mol of n-utillty, 1 pray the compounds of formula (IX). In addition, use 1-3 mol of the ketone of the above formula (Xa) or aldehyde of the above formula (Xb) 1 pray the compounds of formula (IX). The reaction temperature is usually from-78º to 0 ° C, and preferably-78º. The reaction is usually completed within 1 to 24 hours, but the duration of the reaction may be appropriately increased or decreased.

In addition, the compound of the above formula (XI) can be also synthesized by the following method. That is, the compound of the above formula (IX) is subjected to n-utility to get argillite as the intermediate of the reaction, which then interacts in El what stropila, such as venerable (Xc) (where R3is the same as defined above). The compound obtained is subjected to reduction reaction of using sodium borohydride for the synthesis of compounds of the above formula (XI). When the interaction is 2-5 mol, preferably 2 mol of n-utillity to 1 pray the compounds of formula (IX). In addition, use 1-3 mol of amide of the above formula (Xc) 1 pray the compounds of formula (IX). The reaction temperature is usually from-78º to 0 ° C, and preferably-78º. The reaction is usually completed within 1 to 24 hours, but the duration of the reaction may be appropriately increased or decreased. The reaction of repair, use 1-3 mol, preferably 1 mol sodium borohydride to 1 pray the compounds of formula (IX).

The compound of the above formula (IV) (where R3and R4represent the same as defined above) can be synthesized using the compounds of the above formula (XI) in accordance with the method, generally known to experts in this field (Literature: T.W. Greene, John Wiley & Sons Publication, page 518-524, etc.).

The compound of the above formula (Xa)represents, for example, 1-methyl-4-piperidone or similar, and the compound of the above formula (Xb), for example, is 2-formylpyridine-1-carboxylate of the benzyl or the like. The connection of the decree is Noah above formula (Xc), for example, is 4-(N-methoxy-N-methylcarbamoyl)piperidine-1-carboxylate of the benzyl or the like. These compounds are either available commercially or can be synthesized from a commercially available compound by a method generally known to experts in the field, or an equivalent method (Literature: Bioorg. Med. Chem., 2003, 11, 3153, Pamphlet of International Publication WO03/011285, page 60-61, etc.).

Figure 4: Representative method for obtaining compounds of formula (XVI)

Scheme 4

The compound of the above formula (XII) (where Boc is tert-butoxycarbonyl group) can be obtained by subjecting the interaction of the compounds of the above formula (IX) (where Boc is the same as defined above) and vinyltrifluoroborate potassium or vinyltrimethylsilane in a solvent such as N,N-dimethylformamide, 1,4-dioxane, toluene, tetrahydrofuran, methanol, dimethoxyethane or the like, in the presence of a palladium catalyst, such as tetrakis(triphenylphosphine)palladium (0) or dichlorobis(triphenylphosphine)palladium (II). When this method is used vinyltrifluoroborate potassium, the reaction is preferably conducted in the presence of inorganic bases such as sodium carbonate, sodium bicarbonate or potassium carbonate, or organic bases such as triethylamine and diisopropylethylamine reaction, the reaction temperature can be appropriately selected by experts in the field, in accordance with the reagent or the reaction solvent, but the reaction temperature is usually from room temperature to the boiling point of the solvent. The reaction is usually completed within 1 to 24 hours, but the duration of the reaction may be appropriately increased or decreased.

The compound represented by the above formula (XIII) (where Boc is the same as defined above) can be synthesized by treatment of the compound of the above formula (XII) reaction dihydroxypropane in a mixed solvent of acetone and water with the use of osmium tetroxide and N-oxide N-methylmorpholine. Preferably, the reaction is conducted usually at a temperature from 0 ° C to room temperature. The reaction is usually completed within 1-48 hours, but the duration of the reaction may be appropriately increased or decreased.

Optically active substance of the compound represented by the above formula (XIII) can be synthesized by subjecting the compound of formula (XII) slow reactions asymmetric dihydroxypropane (Literature: Chem. Rev., 1994, 94, 2483, etc.) using AD-mix α or β (manufactured by Aldrich orporation) instead of osmium tetroxide as an oxidizing agent.

The compound represented by the above formula (XIV) (where Boc is the same as defined above) can be synthesized by selecting the introduction of the leaving group in the primary hydroxyl group of the compound represented by the above formula (XIII) and then exposed to the compound obtained in the cyclization reaction by heating in a solvent, such as dichloromethane, chloroform, toluene, tetrahydrofuran or the like, in the presence or inorganic bases such as sodium hydroxide, potassium hydroxide, potassium carbonate or the like, or organic bases such as triethylamine, diisopropylethylamine, pyridine or the like. In this case, methanesulfonyl group, p-toluensulfonyl group or the like can be used as leaving groups. In response to the introduction of the leaving group is 1-3 moles, preferably 1.1 mol methanesulfonanilide or p-toluensulfonate, 1 pray compounds represented by the above formula (XIII), the reaction Temperature is from 0 ° C to room temperature, and preferably, 0OC. The reaction is usually completed within 1 to 24 hours, but the duration of the reaction may be appropriately increased or decreased.

The compound represented by the above formula (XV) (where Nu is the Deputy derived from a nucleophilic agent, such as tert-butylamine, and Boc represents the same as defined above) can be synthesized by the reaction of epoxide represented by the above formula (XIV) with a nucleophilic agent in a solvent such as methanol, ethanol or water. When the reaction is used for 1 mol of excess, preferably about 10 mol nucleophilic agent,1 pray compounds represented by the above formula (XV). The reaction temperature can be appropriately selected by experts in the field in accordance with the starting compound or reaction solvent, but the reaction temperature is usually from room temperature to the boiling point of the solvent, and preferably from -40 º C to the boiling point of the solvent. The reaction is usually completed within 1 to 24 hours, but the duration of the reaction may be appropriately increased or decreased. Nucleophilic agent in the reaction, for example, represents a tert-butylamine, piperazine or the like. They are either available commercially or can be synthesized from a commercially available compound by a method generally known to experts in the field, or an equivalent method.

The compound represented by the above formula (XVI) where Nu is the same as defined above) can be synthesized from a compound represented by the above formula (XV) in accordance with the method, generally known to experts in this field (Literature: Protective Groups in Organic Synthesis, the third edition, written by T.W. Greene, John Wiley & Sons Publication, page 518 - 524, etc.).

In the methods of production described in the above schemes 1 to 4, the desired compound can be obtained by using a method commonly used in synthetic organic chemistry, such as, when necessary, SPO the Oba protect or unprotect functional groups [e.g., see Protective Groups in Organic Synthesis, the third edition, written by T.W. Greene, John Wiley & Sons Publication].

Next will be explained an inhibiting effect on PLK1 and inhibitory effects on cell proliferation, the compounds of formula (I).

1. Measurement of inhibitory effect against the activity of PLK1 (Method A)

(1) Obtaining PLK1-T210D

It was known that the 210-th codon of human PLK1, which initially encodes threonine, can be replaced by an active type site change in aspartic acid [Molecular and Cell Biology (Mol. Cell. Biol.), 17 th edition, 3408 (1997)]. To obtain active human PLK1 protein has been mutated cDNA PLK1 (PLK1-T210D), 210-th codon which encodes aspartic acid substitution of the base 210-th codon cDNA of human PLK1. Received baculovirus, for which the N end of the cDNA PLK1-T210D fused with GST (glutathione S-transferase), and then PLK1-T210D, transfected into insect cells Spodoptera frugiperda (Sf) 9 was highly expressed in the form of protein, hybridized with GST. The cells were recovered and suspended in Lisina buffer (buffer 50 mm Tris-hydrochloric acid (pH 7.4)/150 mm sodium chloride/1 mm EDTA (ethylenediaminetetraacetic acid)/1 mm dithiothreitol/0,1% polyoxyethylenesorbitan) for cell disruption apparatus for ultrasonic treatment, and the supernatant was removed after centrifugation. The supernatant was subjected to reaction for glutathione beads, separo the s and then the beads were washed Lisinym buffer. After this, the beads were subjected to interaction with Lisinym buffer containing a precision protease (manufactured by GE Heakthcare Bioscience Company) to extract the supernatant.

(2) Measurement of activity of PLK1-T210D

For measuring the activity of PLK1-T210D as the substrate used a synthetic peptide (arginine-arginine-arginine-aspartic acid-glutamic acid-leucine-methionine-glutamic acid-alanine-serine-phenylalanine-alanine-aspartic acid-glutamine-glutamic acid-alanine-lysine-valine) (SEQ.ID.NO.:1), which changed the surrounding serine amino acid sequence of sequence No. 198 CDC25C, noted as the site for the substrate of PLK1 [EMBO Report, 3rdedition, 341 (2002)].

The reaction was carried out in accordance with the method Toyoshima-Morimoto et al. [Nature, Vol. 410, 215-220, (2001)]. The volume of the reaction solution was 21.1 μl, and the composition of the reaction buffer was 20 mm buffer Tris-hydrochloric acid (pH 7.4)/10 mm of magnesium chloride/0.5 mm of dithiothreitol/1 mm EGTA (ethylene glycol-bis(beta-aminoethylamino)-N,N,N',N'-tetraoxane acid). To it was added the purified PLK, of 1.50 μm substrate peptide, 50 μm not labeled adenosine triphosphate (ATP) and 1 µci labeled [γ-33P] ATP (from 2000 to 4000 CI/mmol) for the reaction at 25 º C for 20 min. Then the reaction system was added 10 ál 350 mm phosphate buffer to stop p the shares. The resulting solution was applied through a mesh phosphocellulose filter on a 96-well plate. After washing phosphocellulose filter 75 mm phosphate buffer, the filter was dried to measure the radioactivity in a liquid scintillation counter. Not labeled labeled ATP and [γ-33P] ATP were purchased by the company Amersham Bioscience Corp., and net phosphocellulose filter bought the company Millipore Corp.

Adding a connection in accordance with the invention to the reaction system was performed by the addition of 1.1 μl of the solution obtained preliminary dissolution of dimethylsulfoxide at a concentration 20 times the final concentration. The control provided by the addition of 1.1 µl of DMSO to the reaction system.

Determined the size of the IC50compounds in accordance with the invention for determining the activity of PLK1-T210D, and the results are shown below in table 1.

Table 1
# examples of compounds in accordance with the present inventionThe inhibiting effect of PLK1-T210D (nm)
84,1
157,0
2011

2. Measurement of inhibitory effect against the activity of PLK1 (Method)

(1) Obtaining PLK1 (wild-type)

Human PLK1 bought the company Carna Bioscience Inc. In accordance with the product information from Carna Bioscience Inc., this enzyme is an enzyme obtained by the preparation of baculovirus for which the N end of the cDNA of full length wild-type PLK1 fused with GST (glutathione S-transferase), with subsequent transfection of highly expressing PLK1 in the cell of the insect in the form of protein, hybridized with GST., and then carrying out purification using chromatography on glutathione-sepharose.

(2) Measurement of activity of PLK1 (wild-type)

For measuring the activity of PLK1 as a substrate for PLK1, used a synthetic peptide (arginine-arginine-arginine-aspartic acid-glutamic acid-leucine-methionine-glutamic acid-alanine-serine-phenylalanine-alanine-aspartic acid-glutamine-glutamic acid-alanine-lysine-valine) (SEQ.ID.NO.:1) (SEQ.ID.NO.:1), which changed the surrounding serine amino acid sequence of sequence No. 198 CDC25C, noted as the site for the substrate of PLK1 [EMBP Report, 3rdedition, 341 (2002)].

The reaction was carried out in accordance with the method described Toyoshima-Morimoto et al. [Nature, Vol. 410, 215-220, (2001)]. The volume of the reaction solution was 10.5 μl, and the composition of the reaction buffer was: 0 mm buffer Tris-HCl (pH 7.4)/10 mm of magnesium chloride/0.5 mm of dithiothreitol/1 mm EGTA (ethylene glycol-bis(beta-aminoethylamino-N,N,N',N'-tetraoxane acid). To it was added the purified PLK1, 20 μm substrate peptide, 10 μm not labeled adenosine triphosphate (ATP) and 0.3 µci labeled [γ-33P] ATP (>2500 CI/mmol) for performing the reaction at the reaction temperature 25 OC for 120 minutes Then the reaction system was added 20 ml of 350 mm phosphate buffer to stop the reaction, and the resulting solution was applied through a mesh phosphocellulose filter 384-well plate. After washing phosphocellulose filter 75 mm phosphate buffer and subsequent drying, the radioactivity was measured by liquid scintillation counter. Not labeled and labeled [γ-33P] ATP and net phosphocellulose filter were purchased respectively from GE Healthcare Bio-Sciences and Millipore Corporation.

Adding the compounds of the present invention to the reaction system was performed by addition of 0.5 μl of a solution obtained preliminary dissolution connection dimethylsulfoxide at a concentration 20 times the final concentration. The control provided by the addition of 0.5 μl of DMSO to the reaction system.

Determined the size of the IC50compounds of the present invention for PLK1 activity, and the results are shown below in table 2.

Table 2
No. of examples connected to the th in accordance with the present invention The inhibiting effect of PLK1 (wild-type) (nm)
22,3
81,4
151,4
261,8
272,6
282,2
2910
353,4
372,4

As shown above, the same results on the inhibitory activity of the compounds according to the invention against PLK1 can be obtained by any method a and method B, and it is clear that inhibiting activity is significantly high.

3. Measurement of inhibitory effect against cell proliferation: measurement of inhibitory activity against PLK1 at the cellular level

(1) a Method of culturing cells

For measuring the activity of PLK1 inhibition of the compounds on the cellular level, used cancer cell line human cervical HeLaS3. HeLaS3 cells were obtained from American type culture Collection (ATSS) and cultured in CO2-incubator saturated steam using the receiving modified Dulbecco eagle medium, containing 10% fetal calf serum, when 37º in the presence of 5% CO2.

(2) Measurement of inhibitory activity of compounds in accordance with the invention

It was reported that PLK1 plays an important role at different stages of the mitotic phase (M-phase) in mammalian cells (Nature Review Molecular Cell Biology (Nat. Rev. Mol. Cell. Biol.), Vol. 5, 429, (2004). Indeed, when mammalian cells are processed siPHK PLK1 to regulate the level of expression, the progression of the cell cycle is inhibited, and thus the cells stop at M phase. At the time, while you investigate the level of phosphorylation of the 10th serine residue on histone H3, which is reputed to be required for chromosome condensation in M phase, it is observed that the level rises to high values. Thus, after treatment of the cells with connection in accordance with the invention, the level of phosphorylation of histone H3 were examined by the method of indirect fluorescence antibody; cells in M phase identified by their level as an indicator for the analysis of the ratio of cells stopped at M phase; and, further, the EC50 value of each compound was calculated to evaluate the activity of PLK1 inhibition at the cellular level.

First, HeLaS3 cells were sown in the treated lysine 96-well plate (Falco Corp.) in proportion 3000 per cell and gave the opportunity to have stabilized Atisa in the above CO 2-incubator. 24 hours after sowing in each well of the tablet was added connection in accordance with the invention in serial dilution and were then given an opportunity to stabilize in the above CO2-incubator. After 18 hours after addition of the compounds in accordance with the invention, the culture medium containing the compound in accordance with the invention in each well of the tablet was removed and then added 100 μl of ice-cold 100% methanol (Wako Pure Chemical Industries, Ltd.) for carrying out the fixation of the cells for 10 minutes and processed to increase the permeability of membranes. Subsequently, the wells of which would be removed methanol, was added 50 μl of 1% BSA/PBS (bovine serum albumin/saline phosphate buffer) and then blocking was performed for 30 minutes. Then for the primary reaction of antibodies in the wells was added 50 μl of 1% BSA/PBS containing 2.5 mg/ml antibodies against posthistory H3 (Ser 10) (Upstate Corp), and the plate was left at room temperature for 90 minutes. After the reaction, each well once washed with PBS; and for the second reaction of the antibodies was added 50 μl of 1% BSA/PBS containing 1.5 mg/ml Cy5 labeled antibodies against rabbit IgG (H+L) (Chemicon) and 10 mg/ml DAPI (Sigma), which is a reagent, dye core, and then left at room temperature for 90 minutes. After the reaction the reactions the config solution in the wells was removed and replaced by 100 μl of PBS and then fluorescence images were captured using a cell analyzer In Cell Analyzer 1000 (manufactured by GM Amersham) for analysis of the ratio of cells in M phase (mitotic index) in each field of view. When it was assumed that the maximum value of the aspect ratio of the cells is stopped in the M phase, which may be the induction of each drug is 100%, the concentration of drug required to induce 50% of these 100%, is defined as ES.

Value EC50received the above method are shown in table 3.

Table 3
# examples of compounds in accordance with the present inventionInhibitory effect against cell proliferation (nm)
22,6
84,6
154,0
205,0
262,9
274,0
283,5
29the 5.7
3511
3713,9
Example # compounds described in the document WO2006/025567Inhibitory effect against cell proliferation (nm)
105118,4
152555,6
15372,3

As shown in table 3, because the connection according to the invention exhibits a strong inhibitory effect against cell proliferation, it is very useful as antitumor agents. Compared with the compounds described in International publication WO2006/025567, it is obvious that the connection according to the invention shows significantly more pronounced inhibitory activity against cell proliferation due to the presence of the following partial structures:

As mentioned above, the connection in accordance with the invention has excellent activity of inhibiting PLK1, and also has a strong inhibitory effect against cell proliferation. Therefore, it is considered to be useful as antitumor agents for the strong inhibition of proliferation of cancer cells. That is, it is believed that the pharmaceutical composition containing the new derivative substituted aminopyrimidine in accordance with the invention, Pharma or is efticiency acceptable salt or ester is effective for treatment of patients suffering from cancer. In addition, the pharmaceutical composition or antitumor agent may contain pharmaceutically acceptable carriers or diluents. In the present description, the term "pharmaceutically acceptable carriers or diluents" refers to excipients [e.g., fats, bee wax, semi-solid or liquid polyol, natural or gidrirovannogo oil, etc.]; water (such as distilled water, particularly distilled water for injection, etc), physiological salt solution, alcohol (e.g. ethanol), glycerol, polyol, an aqueous solution of glucose, mannitol, vegetable oil or the like, additives [e.g., filler, baking powder, binding agent, lubricating agent, wetting agent, stabilizer, emulsifying agent, dispersing agent, preservative, sweetening agent, kasashima agent, flavouring agent or aromatic substance, thickener, diluent, sautereau substance, the solvent or solubilizer, the preparation for the acquisition of the effect of storage, salts to adjust osmotic pressure, covering agent or antioxidant] and the like.

Connection in accordance with the invention can be used as prodrugs containing ester. In the present description, the term "proletar is in" generally refers to a derivative, in which a certain molecule drug chemically modified, which itself does not show physiological activity, but after the introduction of in vivo transformed back into his original drug molecule for the manifestation of the effectiveness of the drug. As a prodrug, an example of the connection in accordance with the invention, the compound of the above formula (I)in which a hydroxyl group azetilirovanna phosphate group or the like. The prodrug and ester can be obtained in accordance with the method known or used by experts in this field.

In addition, as tumors, in which the expected therapeutic effect of the compounds according to the invention, for example, mention can be made of a solid tumor of a person and the like. Examples of solid human cancers include brain cancer, head and neck cancer, esophageal cancer, thyroid cancer, small cell lung cancer, not small cell lung cancer, breast cancer, stomach cancer, cancer of the gall bladder/bile duct, liver cancer, cervical cancer, cancer of the renal pelvis/ureter, bladder cancer, prostate cancer, penile cancer, testes cancer, embryonal cancer, Wilms tumor, skin cancer, malignant melanoma, neuroblastoma, osteosarcoma, sarcomere, soft tissue sarcoma and the like.

Next will be explained the above, the term "its pharmaceutically acceptable salt or ester".

When the connection is in accordance with the invention is used as an antineoplastic or similar connection can be used in the form of its pharmaceutically acceptable salts. Typical examples of pharmaceutically acceptable salts include inorganic salts such as salts with alkali metals such as sodium, potassium and the like: hydrochloride, sulfate, nitrate, phosphate, carbonate, bicarbonate and hyperchlorite; organic acid salts such as acetate, propionate, lactate, maleate, fumarate, tartrate, malate, citrate, and ascorbate; sulfonates such as methanesulfonate, isetionate, bansilalpet and toluensulfonate; salts of acidic amino acids such as aspartate and glutamate; and the like. The preferred salt of the compounds in accordance with the invention is the hydrochloride and the like.

Getting pharmaceutically acceptable salts of the compounds according to the invention can be implemented in appropriate combination of methods that are commonly used in the field of organic synthetic chemistry. In particular, we can mention the method neutral titration of a solution of the compounds in accordance with the invention in free fo the IU with the use of alkaline solution or the like.

Examples of ester compounds in accordance with the invention include methyl ester, complex with ethyl ether and the like. These esters can be obtained by esterification free carboxyl group in accordance with standard methods.

As a form of introduction used when introducing the compound in accordance with the invention as antineoplastic or similar, can be selected in various forms. For instance, oral preparations such as tablet, capsule, powder, granule and liquid; and sterilized liquid parenteral preparations such as solution and suspension, and the like.

In the present invention, the solid preparations can be obtained without modification in the form of tablets, capsules, granules or powder in accordance with standard methods, but can also be obtained using appropriate additives. Examples of additives include sugars such as lactose and glucose; starches such as starches from corn, wheat and rice; fatty acids such as stearic acid; inorganic salts, such as metasilicate sodium aluminate magnesium and anhydrous calcium phosphate; synthetic polymers such as polyvinylpyrrolidone and polyalkyleneglycol; salts of fatty acids such as stearate and calcium stearate is Agnes; alcohols, such as stearyl alcohol and benzyl alcohol; and synthetic derivatives of cellulose, such as methylcellulose, carboxymethylcellulose, ethylcellulose and hypromellose. In addition to these, one could also mention the commonly used additives, such as water, gelatin, talc, vegetable oils and diatomaceous earth and the like.

These solid preparations such as tablet, capsule, granule and powder can generally contain from 0.1 to 100 wt.%, preferably, from 5 to 100 wt.%. the active ingredient.

Liquid preparations can be obtained in the form of suspensions, syrup, injectable preparation or the like, using appropriate additives, which are generally used for liquid preparations, such as water, alcohols, vegetable oils (e.g. soybean oil, peanut oil, sesame oil) and the like.

In particular, examples of suitable solvent or diluent used in the case of parenteral administration by intramuscular injection, intravenous injection or subcutaneous injection, include distilled water for injection, an aqueous solution of lidocaine hydrochloride (for intramuscular injection), physiological saline, aqueous glucose solution, ethanol, liquid for intravenous injection (e.g., an aqueous solution of citric key is lots sodium citrate and the like), an electrolyte solution (for example, liquid for infusion or intravenous injection) and the like and their mixed solutions.

These injectables can be represented in the form of powder or compounds with suitable additives, which should be dissolved at the time of application, in addition to the form, which is pre-dissolved. Such injectable liquid may typically contain from 0.1 to 10% wt. the active ingredient.

Liquid for oral administration, such as suspension, syrup or the like, may contain from 0.5 to 10% wt. the active ingredient.

For treatment in accordance with the invention, the preferred course of medication may vary in accordance with the form of the introduction of compounds represented by formula (I), subject to application of the compounds represented by formula (I), subject to application of the composition containing the compound represented by formula (I), by way of introduction, and other antitumor agents (the funds); and to be treated cancer cells and the conditions of the patient. Specialists in this field can determine the most appropriate treatment in a given condition based on the commonly used treatment and/or consideration of the present description.

The preferred amount of travel is in accordance with the present invention, subject to the introduction, in practice, can respectively increase or decrease in accordance with the subject application type of connection, type of mixed composition, frequency of administration, subject to certain treatment area and condition of the patient. For example, the daily dose for an adult in the case of oral administration is from 10 to 500 mg, and in the case of parenteral administration, preferably intravenous, 10 to 100 mg/D. in Addition, the frequency of injection may vary depending on route of administration and symptoms, but the introduction can be carried out once or fractional 2-5 servings.

The course of the compounds represented by formula (I), and other anticancer agents to be used in combination, are not specifically limited, but experts in this field, if necessary, can be appropriately determined in accordance with the public literature.

EXAMPLES

Further, the present invention will be described in more detail with reference to examples, but the invention is in no way intended to limit the present examples. Examples of thin-layer chromatography was performed using chromatographs with silica gel Silica gel60F254(Merck & Co., Inc.) and NH (Fuji Silysia Chemical, Ltd.) for a tablet and a UV detector for detection. As silica gel for column use the Wali Wakogel TMC-300 or C-200 (Wako Pure Chemical Industries, Ltd.), NH (Fuji Silysia Chemical, Ltd.), Biotage Si or Biotage NH (Biotage), or Purif-Pack (MORITEX). For the preparative liquid chromatography in reversed-phase as columns used CombiPrep Pro C18 (YMC) and the mobile phase used an aqueous solution of 0.1% triperoxonane acid and 0.1% solution of acetonitrile triperoxonane acid. MS (mass spectrometry) spectra used devices JMS-SX102A (JEOL, Co. Ltd.) or QUATTRO II (Micromass)or LC-MS (liquid chromatography mass spectrometry) used the ZMD instrument (Micromass) for measurement. For NMR spectra were using dimethyl sulfoxide as an internal standard in the case of measurements in deuterated solution of dimethyl sulfoxide, tetramethylsilane was used as internal standard in the case of measurements in deuterated solution of chloroform and methanol was used as internal standard in the case of measurements in deuterated solution of methanol. In addition, the spectrometer, such as a Mercury 400 (400 MHz; Varian, Inc.), Inova 400 (400 MHz; Varian, Inc.), or JNM-AL400 (400 MHz; JEOL, Co. Ltd.) used for measurement. All 8 values were expressed in ppm

Values abbreviations used in the examples below.

s: Singlet

d: Doublet

dd: Double doublet

t: Triplet

dt: Double triplet

q: Quartet

dq: Double Quartet

quint: Quintet

m: Multiplet

b: Wide

brs: Broad singlet

J: Constant connection

Hz: Hertz

DMSO-d6: Deuterated dimethyl sulfoxide

CDCl3: Deuterated chloroform

CD3OD: Deuterated methanol

RT: retention Time

Hereinafter in the present description, the structural formulas of examples 1-38 will be shown in tables 4-8. In joining tables marked with * is an asymmetric carbon atom, which is associated with R3, R4and OH, indicate that one of their asymmetric carbon atoms are in R-form, while the other presents in the S-form.

However, examples 13-16 are shown as follows. In table 5 compounds marked with ** around an asymmetric carbon atom, which is associated with R3, R4and OH, indicate that the asymmetric carbon atoms are the same isomers, or R-form or S-form. Meanwhile compounds marked with ***, indicate that their asymmetric carbon atoms are the same isomers, or R-form or S-form, but they are isomers that differ from compounds marked with **.

Table 4

Table 5

Table 6

Table 7

Table 8

Example 1

Synthesis of 2-[((1S)-1-{4-[2-(dimethylamino)-1-hydroxyethyl]phenyl}ethyl)amino]-4-(8-methylimidazo[1,2-a]pyridine-3-yl)pyrimidine-5-carbonitrile [1] (hereinafter referred to as compound [1])

(1) 2 g S-(-)-1-(4-bromophenyl)ethylamine are dissolved in 20 ml of chloroform and add triethylamine. To it add 2,62 g of di-tert-BUTYLCARBAMATE in the condition ice cooling, and the mixture is stirred for 30 minutes at room temperature. The reaction solution was diluted with 300 ml ethyl acetate and washed with water and saturated brine in this order, and the obtained organic layer is dried over anhydrous magnesium sulfate. The insoluble matter is filtered off, the filtrate is concentrated under reduced pressure and the resulting residue is dissolved in a small amount of chloroform and utverjdayut hexane to obtain 2.6 g of tert-butyl[(1S)-1-(4-bromophenyl)ethyl]carbamate [1-1] (hereinafter referred to as the compound [1-1]) in the form of a white solid.

(2) a Mixture of 600 mg of the compound [1-1], 75 mg dichlorobis(triphenylphosphine)palladium (II), 743 mm tributyl(1-ethoxyphenyl)tin and 3 ml of 1,4-dioxane is stirred overnight at 100ºC. After settling for cooling, the insoluble matter is filtered off, the filtrate is concentrated under reduced pressure. The resulting residue is purified by chromatography on a column of silica gel (eluent: hexane/ethyl acetate = 8/2) to obtain 367 mg of tert-butyl[(1S)-1-(4-acetylphenyl)ethyl]carbamate [1-2] (hereinafter referred to as the compound [1-2]) as a colourless solid.

(3) 984 mg of bromide of benzyltrimethylammonium dissolved in a mixed solvent of 3 ml of chloroform and 2 ml of methanol, and then add 141 μl of bromine. To it add the solution obtained by dissolving 363 mg of the compound [1-2] in a mixed solvent of 4 ml of chloroform and 0.8 ml of methanol. The reaction mixture is stirred for 30 minutes at 40 ºC. After settling for cooling water added to the reaction solution, which was extracted with chloroform. The organic layer was washed with nassen the m brine and dried over anhydrous sodium sulfate. The insoluble matter is filtered off, the filtrate is concentrated under reduced pressure and the resulting residue purified by chromatography on a column of silica gel (eluent: hexane/ethyl acetate = 7/3) to obtain 170 mg of tert-butyl{(1S)-1-[4-(bromoacetyl)phenyl]ethyl}carbamate [1-3] (hereinafter referred to as the compound [1-3]) in the form of a colorless oily product.

(4) 50 mg of the compound [1-3] are dissolved in 0.5 ml N,N-dimethylformamide and added 365 ál of dimethylamine (2.0 M solution of tetrahydrofuran). The mixture is stirred over night at room temperature and then the reaction solution was added saturated aqueous sodium hydrogen carbonate solution and the solution extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The insoluble matter is filtered off, the filtrate is concentrated under reduced pressure and the resulting residue purified preparative thin-layer chromatography to obtain to 26.3 mg of tert-butyl{(1S)-1-[4-(N,N-dimethylglycine)phenyl]ethyl}carbamate [1-4] (hereinafter referred to as compound [1-4]) as a colorless oily product.

(5) to 26.3 mg of the compound [1-4] are dissolved in 1.5 ml of methanol, added to 16.2 mg of sodium borohydride and the mixture is stirred for 30 minutes at room temperature. To the reaction solution was added saturated aqueous solution of hydrocarbon is the sodium and the solution is extracted with a mixed solvent of chloroform and methanol (mixing ratio: 9/1). The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The insoluble matter is filtered off and the filtrate is concentrated under reduced pressure to obtain tert-butyl((1S)-1-{4-[2-(dimethylamino)-1-hydroxyethyl]phenyl}ethyl)carbamate [1-5] (hereinafter referred to as compound [1-5]). Connection [1-5] was used in subsequent reactions without further purification.

(6) 10 g of 4-[(Z)-2-ethoxyphenyl]-2-(methylthio)-5-pyrimidinecarbonitrile (synthesized according to the method described in International publication WO2006/025567, pages 90-91) dissolved in a mixed solvent of 150 ml of 1,4-dioxane and 30 ml of water and then add to it of 8.04 g of N-bromosuccinimide in conditions of ice cooling, and the mixture is stirred for 1.5 hours at room temperature. To the reaction solution was added 4,89 g 2-amino-3-picoline and the mixture is further stirred for 2.5 hours. 200 ml of water is added to the reaction solution for extraction of 2 l of a mixed solvent of chloroform and methanol (mixing ratio: 9/1). The organic layer is washed with water and dried over anhydrous sodium sulfate. Then the insoluble matter is filtered off and the filtrate is concentrated under reduced pressure. The resulting residue is dissolved in a small amount of chloroform and utverjdayut hexane to obtain as 4.02 g of 4-(8-methylimidazo[1,2-a]pyridine-3-yl)--(methylthio)pyrimidine-5-carbonitrile [1-6] (hereinafter referred to as the compound [1-6]) as a light brown solid.

(7) to 20.1 mg of the compound [1-6] are dissolved in 1.5 ml of chloroform and then added to 24.7 mg m-chlorbenzoyl acid in conditions of ice cooling, and the mixture is stirred for 30 minutes at 0OC. To the reaction solution was added saturated aqueous sodium hydrogen carbonate solution and the solution extracted with chloroform. The obtained organic layer was washed with saturated brine and then dried over anhydrous sodium sulfate. The insoluble matter is filtered off and the filtrate is concentrated under reduced pressure to obtain the oxidized form of the compound [1-6]. In a separate flask connection [1-5] are dissolved in 1.5 ml of chloroform and to it was added 1.5 ml triperoxonane acid. The mixture is stirred for 1 hour at room temperature. The reaction solution is concentrated under reduced pressure and the resulting residue is dissolved in methanol, passed through a weak anion exchange resin (Bond Elut Regular type PSA, GL Sciences Inc.) to remove triperoxonane acid, and the solvent is distilled off under reduced pressure. The resulting residue is dissolved in 0.5 ml of tetrahydrofuran and to the resulting solution was added a solution obtained by mixing a 9.9 μl of triethylamine, and the previously obtained oxidized form in 1 ml of chloroform, and the solution is stirred for 3 hours at room temperature. To the reaction solution was added the feast upon the aqueous solution of sodium bicarbonate and the solution extracted with chloroform. The obtained organic layer was washed with saturated brine and then dried over anhydrous sodium sulfate. The insoluble matter is filtered off, the filtrate is concentrated under reduced pressure and then purified preparative thin-layer chromatography (developing solution: chloroform/methanol = 20/1) to obtain 14,5 mg specified in the connection header [1] in the form of a yellow solid.

Spectral data of compound [1] below

1H-NMR (CDCl3) δ: for 9.64-9,62 (m, 1H×1/5), 8,95-a total of 8.74 (m, 1H+1H×4/5), 8,56 (s, 1H×1/5), 8,53 (s, 1H×4/5), 7,43-to 7.15 (m, 5H), 6,64-6,63 (m, 1H), 6,02-6,01 (m, 1H×4/5), 5,85-USD 5.76 (m, 1H×1/5), 5,42-5,33 (m, 1H+1H×1/5), 5,16-5,12 (m, 1H×4/5), 4,74-4,69 (m, 1H), 2,69 (s, 1H×3/5), 2,64 (s, 2H+1H×2/5), a 2.36 (s, 3H), 2,03 and 1.80 (m, 2H), and 1.63 (d, J=6.8 Hz, 3H)

wt.: 442 (M+1)+.

Example 2

Synthesis of 2-[((1S)-1-{4-[(1S)-2-(tert-butylamino)-1-hydroxyethyl]phenyl}ethyl)amino]-4-(8-ethylimidazole[1,2-a]pyridine-3-yl)pyrimidine-5-carbonitrile [2] (hereinafter referred to as compound [2])

(1) a Mixture of 1.0 g of compound [1-1], 892 mg vinyltrifluoroborate potassium, 468 mg dichlorobis(triphenylphosphine)palladium (II), 10 ml of a 2.0m aqueous solution of sodium carbonate and 20 ml of N,N-dimethylformamide is stirred overnight at 90 º. After settling for cooling water added to the reaction solution, extracted with ethyl acetate. The obtained organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. Nerator is that substance is filtered off, the filtrate is concentrated under reduced pressure and the resulting residue purified by chromatography on a column of silica gel (eluent: hexane/ethyl acetate = 100/0-75/25) to obtain 485 mg of tert-butyl[(1S)-1-(4-vinylphenol)ethyl]carbamate [2-1] (hereinafter referred to as compound [2-1]) in the form of a white solid.

(2) to 25.3 g of a mixture of AD-mix-alpha (manufactured by Aldrich Corporation) are added to a mixed solvent of 110 ml of tert-butanol and 110 ml of water to obtain a suspension. It adds a 4,34 g connection [2-1] in conditions of ice cooling and the mixture is stirred for 24 hours at the same temperature. To the reaction solution was added 25 g of sodium sulfite, which is stirred for 30 minutes at 0 ° C and then extracted with chloroform. The resulting organic layer is dried over anhydrous sodium sulfate. The insoluble matter is filtered off, the filtrate is concentrated under reduced pressure and the resulting residue purified by chromatography on a column of silica gel (eluent: chloroform/methanol = 100/0-90/10) to obtain 4,32 g of tert-butyl[((1S)-1-{4-[(1S)-1,2-dihydroxyethyl]phenyl}ethyl)carbamate [2-2] (hereinafter referred to as compound [2-2]) in the form of a white solid.

(3) 4,32 g connection [2-2] are dissolved in 50 ml of pyridine and to it add 3,66 p-toluensulfonate in conditions of ice cooling. The reaction mixture was stirred over night at 0 ° C, we use the t water and the mixture is then extracted with ethyl acetate and the resulting organic layer is dried over anhydrous sodium sulfate. The insoluble matter is filtered off, the filtrate is concentrated under reduced pressure and then the resulting residue is purified by chromatography on a column of silica gel (eluent: hexane/ethyl acetate = 50/50-0/100) to obtain of 6.52 g of 4-methylbenzenesulfonate (2S)-2-(4-{(1S)-1-[(tert-butoxycarbonyl)amino]ethyl}phenyl}-2-hydroxyethyl [2-3] (hereinafter referred to as compound [2-3]) as a colorless amorphous substance.

(4) of 6.52 g of compound [2-3] is dissolved in 44,4 ml of chloroform, add a solution obtained by dissolving 2.4 g of sodium hydroxide in 5,54 ml of water, and add 203 mg of tetrabutylammonium hydrosulfate. The reaction mixture was stirred over night at room temperature, there was added water and the mixture extracted with ethyl acetate. The obtained organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The insoluble matter is filtered off, the filtrate is concentrated under reduced pressure and the resulting residue purified by chromatography on a column of silica gel (eluent: 50% chloroform-hexane/ethyl acetate = 100/0-75/25) to obtain 4.4 g of tert-butyl((1S)-1-{4-[(2S)-oxiran-2-yl]phenyl}ethyl)carbamate [2-4] (hereinafter referred to as compound [2-4]) in the form of a white solid.

(5) 4.4 g of compound [2-4] are dissolved in 40 ml of ethanol, is added 20 ml of tert-butylamine and the mixture is stirred for 3 days at 50'C. The reaction is Astor concentrated and the resulting residue purified by chromatography on a column of silica gel (eluent: hexane/ethyl acetate = 100/0-0/100) to obtain 3.1 g of tert-butyl((1S)-1-{4-[(1S)-2-(tert-butylamino)-1-hydroxyethyl]phenyl}ethyl)carbamate [2-5] (hereinafter referred to as compound [2-5]) in the form of a white solid.

(6) 4,89 g of 4-[(Z)-2-ethoxyphenyl]-2-(methylthio)-5-pyrimidinecarbonitrile (synthesized according to the method described in International publication WO2006/025567, pages 90-91) dissolved in a mixed solvent of 50 ml of 1,4-dioxane and 5 ml of water, then add to it 3,93 g of N-bromosuccinimide in conditions of ice cooling and the mixture is stirred for 1 hour at room temperature. To the reaction solution was added 2.7 g of 3-ethylpyridine-2-amine (synthesized according to the method described in International publication WO2006/025567, page 142) and the solution stirred overnight at room temperature. To the reaction solution was added saturated aqueous sodium hydrogen carbonate solution, the solution is extracted with chloroform and the organic layer is dried over anhydrous sodium sulfate. The insoluble matter is filtered off and the filtrate is concentrated under reduced pressure. To the obtained residue, add diethylether and the resulting solution was stirred for 3 hours. Thus obtained solid is collected by filtration and dried under reduced pressure to obtain 4,46 g of 4-(8-ethylimidazole[1,2-a]pyridine-3-yl)-2-(methylthio)pyrimidine-5-carbonitrile [2-6] (hereinafter referred to as compound [2-6]) as a pale yellow solid./p>

(7) 2 g connection [2-6] are dissolved in 150 ml of chloroform and added 1,95 mg of m-chloroperbenzoic acid in conditions of ice cooling. The mixture is stirred for 30 minutes at 0OC. To the reaction solution was added saturated aqueous sodium hydrogen carbonate solution and the solution extracted with chloroform. The obtained organic layer was washed with saturated brine and then dried over anhydrous sodium sulfate. The insoluble matter is filtered off and the filtrate is concentrated under reduced pressure to obtain the oxidized form of the compound [2-6]. In a separate flask connection [2-5] was dissolved in 20 ml of chloroform and to it was added 10 ml triperoxonane acid in conditions of ice cooling. The reaction solution is stirred for 1 hour at room temperature. The reaction solution is concentrated under reduced pressure, the obtained residue is dissolved in 20 ml of tetrahydrofuran and to it add the solution prepared by mixing 25 ml of triethylamine and previously obtained oxidized form in 20 ml of chloroform, and the mixture is stirred for 1 hour at room temperature. To the reaction solution was added saturated aqueous sodium hydrogen carbonate solution and the solution is extracted with a mixed solvent of chloroform and methanol (mixing ratio 9/1). The obtained organic layer was washed with water and steerageway anhydrous sodium sulfate. The insoluble matter is filtered off, the filtrate is concentrated under reduced pressure and the resulting residue purified by chromatography on a column of silica gel (eluent: chloroform/methanol = 100/0-90/10) to obtain 1.2 g specified in the connection header [2] in the form of a pale yellow solid. 803 mg of the compound [2] is suspended in 20 ml of ethanol and to it add of 1.66 ml of 1N aqueous hydrochloric acid solution to obtain a homogeneous solution. The mixture is concentrated under reduced pressure, the obtained residue is added 20 ml of ethanol and the resulting solution was again concentrated under reduced pressure. Thus obtained solid is dried under reduced pressure at 40 º C and receive the 835 mg hydrochloride specified in the connection header [2] in the form of a pale yellow solid.

Spectral data of compound [2] is presented below.

1H-NMR (DMSO-d6) δ: 9,99 (d, J=6,8 Hz, 1H×1/2), 9,10 (d, J=6.3 Hz, 1H×1/2), 9,04 (d, J=7,3 Hz, 1H×1/2), 8,99 (d, J=7.8 Hz, 1H×1/2), 8,89 (users, 1H), 8,76 (s, 1H), 8,71 (s, 1H×1/2), 8,64 (s, 1H×1/2), 8,42-to 8.40 (m, 1H), 7,46-7,38 (m, 4H), 7,19 (t, J=7,1 Hz, 1H×1/2), 7,07 (t, J=7,1 Hz, 1H×1/2), 6,10 (m, 1H), 5,24 (t, J=7,3 Hz, 1H×1/2), 5,15 (t, J=7,1 Hz, 1H×1/2), to 4.87 (m, 1H), 3,07-of 2.97 (m, 3H), 2,90-to 2.85 (m, 1H), 1,53 (d, J=7,3 Hz, 3H×1/2), 1,50 (d, J=6.8 Hz, 3H×1/2), of 1.33 (t, J=7,6 Hz, 3H×1/2), of 1.30 (t, J=7,3 Hz, 3H×1/2), of 1.29 (s, 9H×1/2), of 1.26 (s, 9H×1/2)

wt.: 484 (M+1)+.

Example 3

Synthesis of 2-[((1S)-1-{4-[(1R)-2-(tert-butylamino)-1-hydroxyethyl]phenyl}ethyl)amino]-4-(8-ethylimidazole[1,2-a]pyridine-3-yl)pyrimidine-5-carbonitrile [3] (hereinafter referred to as compound [3]).

(1) 2.5 g of tert-butyl((1S)-1-{4-[(1R)-2-(tert-butylamino)-1-hydroxyethyl]phenyl}ethyl)carbamate [3-1] (hereinafter referred to as compound [3-1]) are obtained in the form of a white solid matter from 4,14 g connection [2-1] and 24 g of a mixture of AD-mix-β (manufactured by Aldrich Corporation), in accordance with the methods of example 2-(2)-(5).

(2) of 1.17 g of the hydrochloride of compound [3] obtained as a pale yellow foamy product of 1.5 g of compound [2-6] and 1.56 g of compound [3-1] in accordance with the method of example 2-(7).

Spectral data of compound [3] is presented below.

1H-NMR (DMSO-d6) δ: 9,98 (d, J=6,8 Hz, 1H×1/2), 9,04 (d, J=8,3 Hz, 1H), 9,01 (d, J=8,3 Hz, 1H×1/2), 8,97-of 8.92 (m, 1H), 8,76 (s, 1H×1/2), 8,76 (s, 1H×1/2), 8,71 (s, 1H×1/2), 7,49 (d, J=6.3 Hz, 1H×1/2), 7,44-7,37 (m, 5H), 7,21 (t, J=7,3 Hz, 1H×1/2), was 7.08 (t, J=7,3 Hz, 1H×1/2), 6,11 (users, 1H×1/2), 5,27-5,20 (m, 1H×1/2), 5,17-5,10 (m, 1H×1/2), 4,89-is 4.85 (m, 1H), 3,05-2,95 (m, 3H+1H×1/2), 2,91 is 2.80 (m, 1H×1/2), 1,53-1,49 (m, 3H), 1,34-of 1.30 (m, 3H), of 1.28 (s, 9H×1/2), 1,25 (s, 9H×1/2),

wt.: 484 (M+1)+.

Example 4

Synthesis of 2-[((1S)-1-{4-[(1R)-2-(tert-butylamino)-1-hydroxyethyl]phenyl}ethyl)amino]-4-(8-deformity)imidazo[1,2-a]pyridine-3-yl)pyrimidine-5-carbonitrile [4] (hereinafter referred to as the compound [4]).

(1) to 7.15 g of 4-(8-formylamino[1,2-a]pyridine-3-yl)-2-(methylthio)pyrimidine-5-carbonitrile [4-1] (hereinafter referred to as compound [4-1]) are obtained as a pale brown solid from 5,69 g 2-amino-3-formylpyridine and 10 g of 4-[(Z)-2-ethoxyphenyl]-2-(methylthio)-5-pyrimidinecarbonitrile in accordance with the ways the ohms of example 1-(6).

(2) 5 g of compound [4-1] is suspended in 200 ml of chloroform is then added to 7.8 ml TRIFLUORIDE bis(2-methoxyethyl)uminosity in conditions of ice cooling and the mixture is stirred at the same temperature. After about 30 minutes the reaction mixture, which turned into a transparent brown solution was additionally stirred for 30 minutes and then there was added 300 ml of a saturated aqueous solution of sodium bicarbonate. The organic layer and the aqueous layer was separated and the aqueous layer was extracted with a mixed solvent of chloroform and methanol (mixing ratio 9/1). The resulting solution was combined with the previous organic layer, which was washed with water and dried over anhydrous sulfate magic. The insoluble matter is filtered off, the filtrate is concentrated under reduced pressure and the resulting residue purified by chromatography on a column of silica gel (eluent: chloroform/ethyl acetate = 100/0-30/70). The solvent is evaporated, then dissolved in a small amount of chloroform, and to it add hexane for curing, thereby obtaining 2,03 g of 4-[8-(deformity)imidazo[1,2-a]pyridine-3-yl]-2-(methylthio)pyrimidine-5-carbonitrile [4-2] (hereinafter referred to as compound [4-2]) as a brown solid.

(3) 12 mg specified in the header of unity [4] obtained as a white foamy product of 20 mg of compound [4-2] and 1 mg of the compound [3-1] in accordance with the method of example 1-(7).

Spectral data of compound [4] is presented below.

1H-NMR (DMSO-d6) δ: 10,20 (d, J=7,3 Hz, 1H×1/2), which is 9.09 (d, J=7,3 Hz, 1H×1/2), 9,05 (d, J=7,3 Hz, 1H×1/2), 8,96 (d, J=7,3 Hz, 1H×1/2), 8,78 (s, 1H×1/2), 8,77 (s, 1H×1/2), a total of 8.74 (s, 1H×1/2), 8,63 (s, 1H×1/2), 7,86 (d, J=7,3 Hz, 1H×1/2), 7,78 (d, J=7,3 Hz, 1H×1/2), 7,51 (t, J=54,6 Hz, 1H×1/2), was 7.45 (t, J=54,1 Hz, 1H×1/2), 7,37-7,29 (m, 5H+1H×1/2), 7,12 (t, J=7,3 Hz, 1H×1/2), and 5.30-5,04 (m, 2H), 4,51 is 4.45 (m, 1H), 2,60 is 2.51 (m, 2H), 1,54-1,49 (m, 3H), and 1.00 (s, 9H×1/2), of 0.94 (s, 9H×1/2),

wt.: 506 (M+1)+.

Example 5

Synthesis of 2-[((1S)-1-{4-[hydroxy(pyridin-2-yl)methyl]phenyl}ethyl)amino]-4-(8-methylimidazo[1,2-a]pyridine-3-yl)pyrimidine-5-carbonitrile [5] (hereinafter referred to as compound [5]).

(1) 500 mg of the compound [1-1] dissolved in 10 ml of tetrahydrofuran and cooled to-78º. Then to it add 2,33 ml n-utility (1,57M solution of hexane). After 1 hour stirring at the same temperature to the resulting white suspension type 193 μl of picolinamides and the suspension is stirred overnight while warming back to room temperature. To the reaction mixture 50 ml of water and the mixture is extracted with 200 ml of ethyl acetate. The obtained organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. Then the insoluble matter is filtered off, the filtrate is concentrated under reduced pressure. The resulting residue is purified by chromatography on a column of silica gel (eluent: hexane/ethyl acetate = 100/0-30/70) to gaining the 212 mg of tert-butyl((1S)-1-{4-[hydroxy(pyridin-2-yl)methyl]phenyl}ethyl)carbamate [5-1] (hereinafter referred to as compound [5-1]) as a pale brown oily product.

(2) 24 mg specified in the connection header [5] obtained as a gray solid (58 mg of the compound [5-1] and 41 mg of the compound [1-6] in accordance with the method of example 1-(7).

Spectral data of compound [5] is presented below.

1H-NMR (DMSO-d6) δ: 9,95 (d, J=6,8 Hz, 1H×1/2), to 8.94 (d, J=7,1 Hz, 1H×1/2), 8,88 (d, J=7.8 Hz, 1H×1/2), 8,75-to 8.70 (m, 1H+1H×1/2), 8,67 (s, 1H×1/2), 8,56-8,55 (m, 1H×1/2), 8,42-8,35 (m, 1H), to 7.77-to 7.67 (m, 1H), 7,56-7,51 (m, 1H), 7,42-7,25 (m, 5H), 7,21-to 7.15 (m, 1H), 7,11 (t, J=6,8 Hz, 1H×1/2), 6,68-of 6.61 (m, 1H×1/2), 6,03-6,00 (m, 1H), 5,66-the 5.65 (m, 1H), 5,19 (Quint., J=7,1 Hz, 1H×1/2), 5,02 (Quint., J=6,8 Hz, 1H×1/2), 2,58 (s, 3H×1/2), 2,52 (s, 3H×1/2), for 1.49 (d, J=7,1 Hz, 3H×1/2), of 1.45 (d, J=6.8 Hz, 3H×1/2)

wt.: 462 (M+1)+.

Example 6

Synthesis of 2-[((1S)-1-{4-[hydroxy-2-(1-methylpiperidin-4-yl)ethyl]phenyl}ethyl)amino]-4-(8-methylimidazo[1,2-a]pyridine-3-yl)pyrimidine-5-carbonitrile [6] (hereinafter referred to as compound [6]).

(1) 43 mg of 4-{2-[4-((1S)-1-{[5-cyano-4-(8-methylimidazo[1,2-a]pyridine-3-yl)pyrimidine-2-yl]amino}ethyl)phenyl]-2-hydroxyethyl}piperidine-1-carboxylate of benzyl [6-1] (hereinafter referred to as compound [6-1]) obtained as a pale-yellow solid from 300 mg of the compound [1-1], 516 mg 1-benzyloxycarbonyl-4(formylmethyl)piperidine (synthesized in accordance with the method disclosed in European patent publication No. 0367110, pages 108-109) and 41 mg of the compound [1-6], in accordance with the method of example 5.

(2) 21 mg of the compound [6-1] is dissolved in a mixed solvent of 3 ml of tetrahydrofuran and 3 ml of methanol, then to it add 20 mg of the carbon catalyst of 20% palladium hydroxide and the mixture is stirred for 2 hours at room temperature in a hydrogen atmosphere. The catalyst was filtered through celite and the filtrate concentrated under reduced pressure. To the obtained residue, add diethylether and thus obtained solid is collected by filtration to obtain 6 mg of 2-({(1S)-1-[4-(1-hydroxy-2-piperidin-4-retil)phenyl]ethyl}amino)-4-(8-methylimidazo[1,2-a]pyridine-3-yl)pyrimidine-5-carbonitrile [6-2] (hereinafter referred to as compound [6-2]).

(3) To a mixture of 2 mg of compound [6-2] and 100 mcg 37% solution of formaldehyde added 200 μl of a solution of methanol containing 4 mg of zinc chloride, is stirred over night at room temperature. To the reaction mixture are added water and chloroform and the organic layer separated from the aqueous layer. The obtained organic layer was washed with saturated aqueous sodium hydrogen carbonate and saturated brine in that order and dried over anhydrous sodium sulfate. The insoluble matter is filtered off and the filtrate is concentrated under reduced pressure. To the obtained residue, add diethylether and the resulting solid collected by filtration to obtain 2.2 mg specified in the connection header [6] as a gray solid.

Spectral data of compound [6] predstavleniya.

1H-NMR (CDCl3) δ: 9,62 (d, J=7,2 Hz, 1H×1/5), 8,92-8,64 (m, 1H+1H×4/5), 8,55 (s, 1H×1/5), to 8.41 (s, 1H×4/5), 7,45-6,55 (m, 6H), 6,23-of 6.20 (m, 1H×4/5), 5,95-5,90 (m, 1H×1/5), 5,40-4,70 (m, 2H), 3.00 and-2,70 (m, 4H), 2,58 (, 3H), of 2.30 (s, 3H), 2,10-of 1.40 (m, 7H), of 1.62 (d, J=6.8 Hz, 3H)

wt.: 496 (M+1)+.

Examples 7 and 8

Synthesis of 4-(8-ethylimidazole[1,2-a]pyridine-3-yl)-2-[((1S)-1-{4-[hydroxy(1-methylpiperidin-4-yl)methyl]phenyl}ethyl)amino]pyrimidine-5-carbonitrile [7] (hereinafter referred to as compound [7]and [8] (hereinafter referred to as compound [8]) (here is the link [7]and the compound [8] are diastereomers. Cm. table 4).

(1) To a mixture of 975 mg of magnesium, 100 μl of brometane and 20 ml of tetrahydrofuran, add a catalytic amount of iodine and the mixture is stirred for about 10 minutes before the disappearance of the brown color of iodine. To it add 20 ml of tetrahydrofuran containing 5.9 g of 4-chloro-1-methylpyridine, and heated for 2.5 hours to boiling in a vessel with reflux condenser. The so-obtained white suspension is cooled to 0 ° C and to it was added 10 ml of tetrahydrofuran containing 2 g of compound [39], (see reference 1). After stirring overnight while gradually warming back to room temperature is added a saturated solution of ammonium chloride and extracted with ethyl acetate. The obtained organic layer was washed with water and saturated brine in that order and dried over anhydrous magnesium sulfate. rastvorimye substance is filtered off, the filtrate is concentrated under reduced pressure and the resulting residue purified by chromatography on a column of silica gel (eluent: chloroform/methanol = 100/0-90/10) to obtain and 2.27 g of tert-butyl((1S)-1-{4-[hydroxy(1-methylpyridin-4-yl)methyl]phenyl}ethyl)carbamate [7-1] (hereinafter referred to as compound [7-1]).

(2) 1.2 g of the mixture specified in the title compounds [7] and [8] is obtained from 1.42 g of compound [7-1] and 1 g of compound [2-6] in accordance with the method of example 1-(7).

(3) 700 mg of a mixture of compounds [7] and [8] separated using column Chiralcel OD-H.

Conditions for optical resolution the following.

Column: Chiralcel OD-H (Daicel Chemical Industries Ltd.), diameter 20 mm, length 250 mm

Eluent: hexane/ethanol/diethylamine = 85/15/0,1.

Flow rate: 15 ml/min

The resulting solution was concentrated under reduced pressure and the residue is dissolved in a small amount of chloroform for curing deethylation by getting 217 mg specified in the connection header [7] (RT = 18,3 minutes) as a white solid and 230 mg specified in the connection header [8] (RT = 24,3 minutes) as a pale yellow solid.

Spectral data of compound [7] and the compound [8] is presented below.

Connection [7]

1H-NMR (DMSO-d6) δ: 9,98 (d, J=6.3 Hz, 1H×2/5), 8,97 (d, J=7,1 Hz, 1H×3/5), of 8.90 (d, J=7,3 Hz, 1H), 8,73 (s, 1H), to 8.70 (s, 1H×2/5), at 8.60 (s, 1H×3/5), 7,42 (d, J=6,1 Hz, 1H×2/5), 7,35-7,33 (m, 2H+1H×3/5), 7,26-7,21 (m 2H), to 7.15 (t, J=7,1 Hz, 1H×2/5), 6,89 (t, J=7,1 Hz, 1H×3/5), 5,24 (Quint., J=7,1 Hz, 1H×2/5), 5,17-of 5.05 (m, 1H+1H×3/5), 4,20 is 4.13 (m, 1H), 3,02 (sq, J=7,6 Hz, 2H×2/5), 2,96 (sq, J=7,6 Hz, 2H×3/5), is 2.74 2.63 in (m, 1H+1H×2/5), 2,50-2,48 (m, 1H×3/5), to 2.06 (s, 3H×2/5), 2,02 (s, 3H×3/5), 1,73-of 1.62 (m, 2H+1H×2/5), of 1.52 (d, J=7,1 Hz, 3H×2/5), for 1.49 (d, J=7,1 Hz, 3H×3/5), 1,32 (t, J=7,6 Hz, 3H×2/5), of 1.28 (t, J=7,6 Hz, 3H×3/5), 1,22 of-1.04 (m, 4H), 0,97-0,94 (m, 1H×3/5)

wt.: 496 (M+1)+.

Connection [8]

1H-NMR (DMSO-d6) δ: 9,98 (d, J=6,1 Hz, 1H×1/2), 8,97 (d, J=7,1 Hz, 1H×1/2), 8,90-8,89 (m, 1H), 8,73 (s, 1H×1/2), 8,73 (s, 1H×1/2), to 8.70 (s, 1H×1/2), at 8.60 (s, 1H×1/2), the 7.43 (d, J=6,1 Hz, 1H×1/2), 7,35-7,33 (m, 2H+1H×1/2), 7,25 (d, J=8,3 Hz, 1H×1/2), 7,22 (d, J=8.0 Hz, 1H×1/2), to 7.15 (t, J=7,1 Hz, 1H×1/2), 6,92 (t, J=7,1 Hz, 1H×1/2), 5,24 (Quint., J=7,1 Hz, 1H×1/2), 5,08-of 5.05 (m, 1H+1H×1/2), 4,20-4,16 (m, 1H), 3,01 (sq, J=7,6 Hz, 2H×1/2), 2,96 (sq, J=7,6 Hz, 2H×1/2), 2,74-of 2.64 (m, 1H+1H×1/2), 2,55 is 2.51 (m, 1H×1/2), to 2.06 (s, 3H×1/2), 2,02 (s, 3H×1/2), 1,72-of 1.55 (m, 2H+1H×1/2), of 1.52 (d, J=7,1 Hz, 3H×1/2), for 1.49 (d, J=7,1 Hz, 3H×1/2), 1,32 (t, J=7,6 Hz, 3H×1/2), of 1.28 (t, J=7,6 Hz, 3H×1/2), 1,22-1,11 (m, 4H), of 1.03 to 1.00 (m, 1H×1/2)

wt.: 496 (M+1)+.

Examples 9 and 10

Synthesis of 4-(8-ethylimidazole[1,2-a]pyridine-3-yl)-2-[((1S)-1-{4-[hydroxy(1-isopropylpiperazine-4-yl)methyl]phenyl}ethyl)amino]pyrimidine-5-carbonitrile [9] (hereinafter referred to as compound [9]and [10] (hereinafter referred to as compound [10]) (here is the link [9] and the compound [10] are diastereomers. Cm. table 5).

(1) 486 mg of the compound [25-3] dissolved in 15 ml of chloroform is then added 2.4 ml of acetone and 728 mg triacetoxyborohydride sodium and the mixture is stirred over night at 50'C. After settling on what I cooling to the reaction solution was added saturated aqueous sodium hydrogen carbonate solution and the solution extracted with chloroform. The obtained organic layer is washed with water and dried over anhydrous magnesium sulfate. The insoluble matter is filtered off, the filtrate is concentrated under reduced pressure and the resulting residue purified by chromatography on a column of silica gel (eluent: chloroform/methanol = 100/0-93/7) to obtain 738 mg of the mixture specified in the title compounds [9] and [10]. The mixture is separated using column Chiralcel OD-H.

Conditions for optical resolution the following.

Column: Chiralcel OD-H (Daicel Chemical Industries Ltd.), diameter 20 mm, length 250 mm

Eluent: hexane/ethanol/diethylamine = 85/15/0,1.

Flow rate: 15 ml/min

The resulting solution was concentrated under reduced pressure and the residue is dissolved in a small amount of chloroform for curing deethylation by receiving 175 mg specified in the connection header [9] (RT = 17 min) as a pale yellow amorphous substance and 390 mg specified in the connection header [10] (RT = 21 minutes) as a gray solid.

Spectral data of compound [9] and the compound [10] is presented below.

Connection [9]

1H-NMR (DMSO-d6) δ: 9,98 (d, J=6,6 Hz, 1H×1/2), of 8.95 (d, J=7,1 Hz, 1H×1/2), 8,90-8,88 (m, 1H), 8,73 (s, 1H×1/2), 8,72 (s, 1H×1/2), to 8.70 (s, 1H×1/2), 8,61 (s, 1H×1/2), 7,42 (d, J=6,8 Hz, 1H×1/2), 7,35-to 7.32 (m, 2H+1H×1/2), 7,26-7,20 (m, 2H), 7,14 (t, J=7,1 Hz, 1H×1/2), 6,89 (t, J=7,1 Hz, 1H×1/2), 5,24 (Quint., J=7,3 Hz, 1H×1/2), 5,06 (Quint., J=7,1 Hz, 1H×1/2), 5,03-free 5.01 (m, 1H), 4,20 of 4.8 (m, 1H×1/2), 4,15-4,12 (m, 1H×1/2), 3,02 (sq, J=7,6 Hz, 2H×1/2), 2,96 (sq, J=7,6 Hz, 2H×1/2), 2,75-2,60 (m, 1H+1H×1/2), 2,58-2,48 (m, 1H×1/2), 1,95-of 1.88 (m, 1H+1H×1/2), 1,76-of 1.73 (m, 1H+1H×1/2), of 1.52 (d, J=the 7.3 Hz, 3H×1/2), 1,50 (d, J=7,1 Hz, 3H×1/2), 1,38-1,25 (m, 1H), 1,32 (t, J=7,6 Hz, 3H×1/2), of 1.27 (t, J=7,6 Hz, 3H×1/2), 1,18-of 1.09 (m, 2H), 1,00-to 0.96 (m, 1H), 0,89-of 0.83 (m, 6H)

wt.: 524 (M+1)+.

Connection [10]

1H-NMR (DMSO-d6) δ: 9,98 (d, J=6,8 Hz, 1H×1/2), 8,96 (d, J=7,1 Hz, 1H×1/2), 8,91-8,88 (m, 1H), 8,73 (s, 1H), 8,71 (s, 1H×1/2), at 8.60 (s, 1H×1/2), the 7.43 (d, J=7.8 Hz, 1H×1/2), 7,35-7,33 (m, 2H+1H×1/2), 7,25-7,20 (m, 2H), to 7.15 (t, J=6,8 Hz, 1H×1/2), 6,92 (t, J=6,8 Hz, 1H×1/2), 5,26 with 5.22 (m, 1H×1/2), 5,09-of 5.06 (m, 1H×1/2), 5,04-5,00 (m, 1H), 4,21-4,16 (m, 1H), 3,02 (sq, J=7,3 Hz, 2H×1/2), 2,96 (sq, J=7,3 Hz, 2H×1/2), 2,74-2,71 (m, 1H×1/2), to 2.67 2.63 in (m, 1H), 2,55-2,48 (m, 1H×1/2), 1,98-of 1.65 (m, 3H), of 1.52 (d, J=7,1 Hz, 3H×1/2), 1,50 (d, J=7,3 Hz, 3H×1/2), 1,35-of 1.26 (m, 1H), 1,32 (t, J=7,6 Hz, 3H×1/2), of 1.28 (t, J=7,6 Hz, 3H×1/2), 1,14-of 1.03 (m, 3H), from 0.88 (d, J=6.3 Hz, 6H×1/2)to 0.85 (d, J=6.6 Hz, 6H×1/2)

wt.: 524 (M+1)+.

Example 11

Synthesis of 4-(6-bromo-8-ethylimidazole[1,2-a]pyridine-3-yl)-2-[((1S)-1-{4-[hydroxy(1-isopropylpiperazine-4-yl)methyl]phenyl}ethyl)amino]pyrimidine-5-carbonitrile [11] (hereinafter referred to as compound [11]).

(1) To a solution obtained by dissolving 360 mg of 3-etlepaludi-2-amine (synthesized according to the method described in International publication WO2006/025567, page 142), in a mixed solvent of 12 ml of 1,4 dioxane and 4 ml of water is added 553 mg of N-bromosuccinimide at 0 ° C and the mixture is stirred for 1.5 hours at the same temperature. Water added to the reaction solution, to the which is extracted with ethyl acetate. Thus obtained organic layer was washed with water and saturated brine in that order and dried over anhydrous sodium sulfate. Then the insoluble matter is filtered off and the filtrate is concentrated under reduced pressure. The resulting residue is purified by chromatography on a column of silica gel (eluent: hexane/ethyl acetate = 75/25) to obtain 394 mg 5-bromo-3-ethylpyridine-2-amine [11-1] (hereinafter referred to as compound [11-1]).

(2) 530 mg of 4-(6-BRM occupational-8 ethylimidazole[1,2-a]pyridine-3-yl)-2-(methylthio)pyrimidine-5-carbonitrile [11-2] (hereinafter referred to as compound [11-2]) is obtained from 388 mg of the compound [11-1] in accordance with the method of example 1-(6).

(3) To a solution obtained by dissolving 2,98 g of compound [40] (see reference 2) in a mixed solvent of 30 ml of tetrahydrofuran and 10 ml of 2-propanol, add 750 mg carbon catalyst 20% palladium hydroxide and the mixture is stirred over night at room temperature in a hydrogen atmosphere. The catalyst was filtered through celite and the filtrate concentrated under reduced pressure to obtain 2.3 g of tert-butyl((1S)-1-{4-[hydroxy(piperidine-4-yl)methyl]phenyl} ethyl)carbamate [11-3] (hereinafter referred to as compound [11-3]). Connection [11-3] used in subsequent reactions without further purification.

(4) 2.14 g of tert-butyl((1S)-1{4-[hydroxy(1-isopropylpiperazine-4-yl)methyl]phenyl}ethyl)carbamate [11-4] (hereinafter referred to as the connection is using [11-4] is obtained from 2.3 g of compound [11-3] and 15 ml of acetone according to the method of example 6-(3).

(5) 41 mg specified in the connection header [11] obtained as a yellow amorphous substance from 70 mg of the compound [11-4] and 63 mg of the compound [11-2] in accordance with the method of example 1-(7).

Spectral data of compound [11] is presented below.

1H-NMR (CDCl3) δ: of 9.89 (s, 1H×5/6), 9,74 (s, 1H×1/6), 8,93 (s, 1H×5/6), 8,86 (s, 1H×1/6), 8,55 (s, 1H×1/6), 8,16 (s, 1H×5/6), 7,41-7,27 (m, 5H), 6,76 (d, J=8.0 Hz, 1H×5/6), of 6.29 (d, J=8.0 Hz, 1H×1/6), 5,35 (users, 1H×1/6), 5,27 (Quint., J=7.5 Hz, 1H×5/6), to 4.38 (d, J=7.5 Hz, 1H), 3,10 (sq, J=7.5 Hz, 2H), 2,98-of 2.72 (m, 5H), 2,14-of 1.92 (m, 3H), 1.69 in (d, J=7.5 Hz, 3H), 1,59-1,50 (m, 1H), 1,43-1,25 (m, 2H), 1,41 (t, J=7.5 Hz, 3H), of 1.02 (d, J=7.5 Hz, 6H)

wt.: 602, 604 (M+1)+.

Example 12

Synthesis of 4-(8-cyclopropylamino[1,2-a]pyridine-3-yl)-2-[((1S)-1-{4-[hydroxy(1-methylpiperidin-4-yl)methyl]phenyl}ethyl)amino]pyrimidine-5-carbonitrile [12] (hereinafter referred to as compound [12]).

(1) 750 mg of 4-(8-cyclopropylamino[1,2-a]pyridine-3-yl)-2-(methylthio)pyrimidine-5-carbonitrile [12-1] (hereinafter referred to as compound [12-1]) obtained as orange solids from 390 mg of 3-cyclopropylmethyl-2-amine (synthesized according to the method described in International publication WO2006/025567, page 142) in accordance with the method of example 1-(6).

(2) 66 mg specified in the connection header [12] obtained as yellow solid from 100 mg of the compound [12-1] and 110 mg of compound [7-1]) in accordance with the method of example 1-(7).

Spectral data of compound [12] p is estaline below.

1H-NMR (CD3OD) δ: 9,85 (d, J=8.0 Hz, 1H×1/3), 8,78-8,73 (m, 1H×2/3), 8,68 (s, 1H×1/3), 8,61 (s, 1H×2/3), 8,43 (s, 1H×2/3), at 8.36 (s, 1H×1/3), 7,40-7,25 (m, 4H), 6,93 (t, J=8.0 Hz, 1H×2/3), 6,87 (d, J=8.0 Hz, 1H×2/3), of 6.71 (d, J=8.0 Hz, 1H×1/3), to 6.67 (t, J=8.0 Hz, 1H×1/3), 5,23 (sq, J=7.5 Hz, 1H×1/3), 5,01 (Quint., J=7.5 Hz, 1H×2/3), 4,28-4,22 (m, 1H), 2,87-a 2.71 (m, 2H×2/3), 2,59 is 2.51 (m, 2H×1/3), 2,39-of 2.36 (m, 1H), 2,16 (s, 3H×1/3), 2,12 (s, 3H×2/3), 1,99-to 1.79 (m, 2H), 1,71 of-1.04 (m, 7H), and 1.56 (d, J=7.5 Hz, 3H×2/3), of 1.06 (d, J=7.5 Hz, 3H×1/3), 0,82-to 0.73 (m, 2H)

wt.: 508 (M+1)+.

Examples 13 and 14

Synthesis of 4-(8-ethylimidazole[1,2-a]pyridine-3-yl)-2-[((1S)-1-(4-{hydroxy[(3R)=1 methylpiperidin-3-yl]methyl}phenyl)ethyl]amino}pyrimidine-5-carbonitrile [13] (hereinafter referred to as compound [13]) and 4-(8-ethylimidazole[1,2-a]pyridine-3-yl)-2-[((1S)-1-(4-{hydroxy[(3S)=1 methylpiperidin-3-yl]methyl}phenyl)ethyl]amino}pyrimidine-5-carbonitrile [14] (hereinafter referred to as compound [14]) (here is the link [13] and the compound [14] are diastereomers. Cm. table 5).

(1) of 11.8 g of benzyl-3-[(4-{(1S)-1-[(tert-butoxycarbonyl)amino]ethyl}phenyl)(hydroxy)methyl]piperidine-1-carboxylate [13-1] (hereinafter referred to as compound [13-1]) are obtained in the form of a mixture of four isomers of 15 g of benzyl(3R()-3-formylpiperidine-1-carboxylate (synthesized according to the method described in International publication WO02/46157) and 16.6 g of the compound [1-1] according to the method of example 5-(1).

(2) for 6.81 g of benzyl-3-[[4-{(1S)-1-{[5-cyano-4-(8-ethylimidazole[1,2-a]pyridine-3-yl)pyrimidine-2-yl]amino}ethyl)phenyl](hydroxy)methyl]piperidin-1-carboxylate [13-2] (hereinafter referred to as compound [13-2]) is obtained from 7,56 g connection [2-6] and 11.8 g of compound [13-1]) in accordance with the method of example 1-(7).

(3) 5 g of 4-(8-ethylimidazole[1,2-a]pyridine-3-yl)-2-[((1S)-1-{4-[hydroxy(piperidine-3-yl)methyl]phenyl}ethyl)amino]pyrimidine-5-carbonitrile [13-3] get out for 6.81 g of compound [13-2] in accordance with the method of example 6-(2). The compound obtained [13-3], which is a mixture of four isomers, purify by chromatography on a column of silica gel (eluent: chloroform/methanol = 100/0-90/10), thereby obtaining of 2.21 g of compound of low polarity (compound, which eluted first in the above conditions) [13-3A] (hereinafter referred to as compound [13-3A]) and 1.88 g of the compound of high polarity (connection, which is then eluted in the above conditions) [13-3b] (hereinafter referred to as compound [13-3b]), each in the form of a mixture of two isomers. Here is the link [13-3A] is a mixture of precursor compounds respectively [13] and [14]and the compound [13-3b] is a mixture of precursor compounds respectively [15] and [16].

(4) 1,89 g of a mixture of compounds [13] and [14] get out of 2.21 g of compound [13-3A] in accordance with the method of example 6-(3). The mixture is separated using column Chirpack AD.

Conditions for optical resolution the following.

Column: Chirpack AD (Daicel Chemical Industries Ltd.), diameter 50 mm, length 5000 mm

Eluent: hexane/2-propanol/diethylamine = 65/35/0,1.

Flow rate: 100 ml/min

The resulting solution was concentrated under reduced pressure and the residue is dissolved in not what olsom the amount of chloroform for curing titilation, through this getting 892 mg specified in the connection header [13] (RT = 15,5 minutes) as a pale yellow solid and 298 mg specified in the connection header [14] (RT = 35 minutes) as a pale yellow solid.

Spectral data of compound [13] and the compound [14] is presented below.

Connection [13]

1H-NMR (DMSO-d6) δ: 9,98 (d, J=6,8 Hz, 1H×1/3), 8,96 (d, J=6,8 Hz, 1H×2/3), 8,89-8,86 (m, 1H), 8,73 (s, 1H), to 8.70 (s, 1H×1/3), 8,61 (s, 1H×2/3), 7,41-7,16 (m, 5H+1H×1/3), 6,89 (t, J=7,1 Hz, 1H×2/3), and 5.30-5,00 (m, 2H), 4,29-4,19 (m, 1H), 3,32 (s, 3H), 3,02-of 2.93 (m, 2H), 2,65-of 2.50 (m, 1H), 2,32-of 2.28 (m, 1H×1/3), 2,12-to 2.06 (m, 1H×2/3), 1,80-of 1.40 (m, 9H), 1.32 to-1,20 (m, 3H)

wt.: 496 (M+1)+.

Connection [14]

1H-NMR (DMSO-d6) δ: 9,90 (m, 1H×2/5), 8,98 at 8.60 (m, 3H+1H×3/5), 7,60-6,85 (m, 6H), 5,18-of 5.05 (m, 2H), 4,30-4,20 (m, 1H), 3,34 (s, 3H), 3,20 is 2.80 (m, 2H), 2,70-of 2.50 (m, 1H), 2,18-of 1.45 (m, 10H), 1,40-1,20 (m, 3H)

wt.: 496 (M+1)+.

Examples 15 and 16

Synthesis of 4-(8-ethylimidazole[1,2-a]pyridine-3-yl)-2-{[(1S)-1-(4-{hydroxy[(3R)-1-methylpiperidin-3-yl]methyl}phenyl)ethyl]amino}pyrimidine-5-carbonitrile [15] (hereinafter referred to as compound [15]) and 4-(8-ethylimidazole[1,2-a]pyridine-3-yl)-2-{[(1S)-1-(4-{hydroxy[(3S)-1-methylpiperidin-3-yl]methyl}phenyl)ethyl]amino}pyrimidine-5-carbonitrile [16] (hereinafter referred to as compound [16]) (here is the link [15] and the compound [16] are diastereomers. Cm. table 5).

921 mg of the mixture specified in the title compounds [15] and [16] is obtained from 917 mg of compound [13-3b] in accordance with the method when the EPA 6-(3). The mixture is separated using column Chiralcel OD-H.

Conditions for optical resolution the following.

Column: Chiralcel OD-H (Daicel Chemical Industries Ltd.), diameter 20 mm, length 250 mm

Eluent: hexane/ethanol/diethylamine = 85/15/0,1.

Flow rate: 20 ml/min

The resulting solution was concentrated under reduced pressure and the residue is dissolved in a small amount of chloroform for curing deethylation by getting 510 mg specified in the connection header [15] (RT = 16,8 minutes) as a pale yellow solid and 253 mg specified in the connection header [16] (RT = 23.1 min) as a yellow solid.

Spectral data of compound [15] and the compound [16] is presented below.

Connection [15]

1H-NMR (DMSO-d6) δ: 10,00 (d, J=6,8 Hz, 1H×2/5), 8,98 (d, J=6,8 Hz, 1H×3/5), 8,92-8,87 (m, 1H), 8,76 (s, 1H), 8,73 (s, 1H×2/5), 8,63 (s, 1H×3/5), 7,46-to 7.15 (m, 5H+1H×2/5), 6,90 (t, J=7,1 Hz, 1H×3/5), a 5.25-of 5.05 (m, 2H), 4,22-4,20 (m, 1H), 3,34 (s, 3H), 3,10-2,80 (m, 2H), 2,70-of 2.50 (m, 1H), 2,15-to 1.60 (m, 10H), 1,39-1,22 (m, 3H)

wt.: 496 (M+1)+.

Connection [16]

1H-NMR (DMSO-d6) δ: 9,90 (m, 1H×2/5), 9,00 at 8.60 (m, 3H+1H×3/5), 7,40-to 6.80 (m, 6H), 5,20-5,00 (m, 2H), 4,20-4,00 (m, 1H), 3,30 (s, 3H), 3,40-3,20 (m, 2H), 2,70-of 1.40 (m, 8H), 1,40-1,20 (m, 5H)

wt.: 496 (M+1)+.

Examples 17 and 18

Synthesis of 2-{[(1S)-1-(4-{hydroxy[(2S)-1-methylpyrrolidine-2-yl]methyl}phenyl)ethyl]amino}-4-(8-methylimidazo[1,2-a]pyridine-3-yl)pyrimidine-5-carbonitrile [17] (hereinafter referred to as the compound [17] and [18] (hereinafter referred to as compound [18]) (here is the link [17] and the compound [18] are diastereomers. Cm. table 6).

(1) 95 mg of benzyl(2S)-2-[(4-{(1S)-1-[(tert-butoxycarbonyl)amino]ethyl}phenyl)(hydroxy)methyl]pyrrolidin-1-carboxylate [17-1] (hereinafter referred to as compound [17-1]) is obtained from 467 mg of benzyl(2S)-2-formylpyridine-1-carboxylate (synthesized according to the method described in the document Bioorg. Med. Chem. 2003, 11, 3153-3164) and 500 mg of the compound [1-1] in accordance with the method of example 5-(1).

(2) 68 mg of benzyl(2S)-2-[[4-((1S)-1-{[5-cyano-4-(8-methylimidazo[1,2-a]pyridine-3-yl)pyrimidine-2-yl]amino}ethyl)phenyl](hydroxy)methyl]pyrrolidin-1-carboxylate [17-2] (hereinafter referred to as compound [17-2]) is obtained from 93 mg of the compound [17-1] and 48 mg of the compound [1-6] in accordance with the method of example 1-(7).

(3) 10 mg 2-{[(1S)-1-(4-(hydroxy[(2S)pyrrolidin-2-yl]methyl}phenyl)ethyl]amino}-4-(8-methylimidazo[1,2-a]pyridine-3-yl)pyrimidine-5-carbonitrile [17-3] (hereinafter referred to as compound [17-3]) obtained from 30 mg of the compound [17-2] in accordance with the method of example 6-(2).

(4) 7 mg of compound [17-3] dissolved in 1 ml of chloroform, then added 4 mg of 37% solution of formaldehyde and 10 mg triacetoxyborohydride sodium and the mixture is stirred for 2.5 hours at room temperature. To the reaction mixture is added saturated aqueous solution of sodium bicarbonate and the mixture extracted with chloroform. The obtained organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. N is soluble substance is filtered off, the filtrate is concentrated under reduced pressure and the resulting residue purified preparative thin-layer chromatography ((developing solution: chloroform/methanol = 20/1), to separate compounds [17] and the compound [18], which are diastereomers. In accordance with the above condition purification receive 3 mg specified in the connection header [17], which represents the connection of low polarity, and 2 mg specified in the connection header [18], which is a compound of high polarity, both in the form of a white solid.

Spectral data of compound [17] and the compound [18] is presented below.

The compound [17]

1H-NMR (CDCl3) δ: 9,63 (d, J=6.3 Hz, 1H×1/5), to 8.94 (s, 1H×1/5), 8,89 (s, 1H×4/5), 8,76 (d, J=6.3 Hz, 1H×4/5), to 8.57 (s, 1/5), 8,53 (s, 1H×4/5), 7,42-to 7.15 (m, 5H), 6,64-6,60 (m, 1H), 6,07-6,05 (m, 1H×4/5), 5,88-5,80 (m, 1H×1/5), are 5.36-a 5.25 (m, 1H+1H×1/5), 5,15-5,11 (m, 1H×4/5), 4,94 (s, 1H), 2,65-to 2.40 (m, 3H), 2,69 (s, 1H×3/5), 2,64 (s, 2H+1H×2/5), 2,15 is 1.70 (m, 6H), of 2.53 (s, 3H), 1,82-of 1.64 (m, 4H), and 1.63 (d, J=7.2 Hz, 3H)

wt.: 468 (M+1)+.

Connection [18]

1H-NMR (CDCl3) δ: for 9.64-9,63 (m, 1H×1/5), 8,94-8,88 (m, 1H+1H×4/5), 8,53 (s, 1H×1/5), charged 8.52 (s, 1H×4/5), 7,43-7,16 (m, 5H), 6,66-6,62 (m, 1H), 6,04-of 6.02 (m, 1H×4/5), of 5.83-of 5.82 (m, 1H×1/5), 5,18-5,13 (m, 1H×4/5), 4,55-4,54 (m, 1H), 3,40-3,20 (m, 1H), 2,69 (s, 1H×3/5), 2,65 (s, 2H+1H×2/5), 2.57 m at 2.45 (m, 6H), of 2.38 (s, 3H), 1,96-of 1.55 (m, 4H), and 1.63 (d, J=7.2 Hz, 3H)

wt.: 468 (M+1)+.

Examples 19 and 20

Synthesis of 4-(8-ethylimidazole[1,2-a]pyridine-3-yl)pyridine-3-yl)-2-{[(1S)-1-(4-{hydroxy[(2R)-1-methylpyrrole the DIN-2-yl]methyl}phenyl)ethyl]amino}pyrimidine-5-carbonitrile [19] (hereinafter referred to as compound [19]and [20] (hereinafter referred to as compound [20]) (here is the link [19]) and the connection [20] are diastereomers. Cm. table 6).

(1) 300 mg of the compound [41] (see reference 3) dissolved in a mixed solvent of 6 ml of tetrahydrofuran and 6 ml of methanol, and then thereto was added 100 mg of the carbon catalyst of 20% palladium hydroxide and the mixture is stirred for 2.5 hours at room temperature in a hydrogen atmosphere. The catalyst was filtered through celite and the filtrate concentrated under reduced pressure. The resulting residue is dissolved in 6 ml of tetrahydrofuran, then added 147 μl of a 37% solution of formaldehyde and 420 mg of triacetoxyborohydride sodium and the mixture is stirred for 1.5 hours at room temperature. To the reaction solution was added saturated aqueous sodium hydrogen carbonate solution, the solution is extracted with a mixed solvent of chloroform and methanol (mixing ratio: 9/1), and the obtained organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. Then the insoluble matter is filtered off and the filtrate is concentrated under reduced pressure to obtain 220 mg of tert-butyl[(1S)-1-(4-{hydroxy[(2R)-1-methylpyrrolidine-2-yl]methyl}phenyl)ethyl]carbamate [19-1] (hereinafter referred to as compound [19-1]).

(2) 15 mg specified in the connection header [19] and 13 mg specified in the connection header [20] obtained as a colorless solid from 73 mg of the compound [19-1] and 65 mg of compound [2-6] matched the following with the method of example 1-(7). In accordance with the terms of purification described in example 1-(7), the compound [19] represents a connection with a low polarity, and the connection [20] represents the connection to the high polarity.

Spectral data of compound [19] and the compound [20] is presented below.

Connection [19]

1H-NMR (CDCl3) δ: 9,67-9,60 (m, 1H×1/5), 8,95-8,89 (m, 1H+1H×4/5), to 8.57 (s, 1H×1/5), charged 8.52 (s, 1H×4/5), 7,45-7,17 (m, 5H), 6,70 is 6.67 (m, 1H), 6,03-of 6.02 (m, 1H×4/5), 5,85-USD 5.76 (m, 1H×1/5), 5,35-of 5.34 (m, 1H×1/5), 5,16-5,13 (m, 1H×4/5), 4,88-to 4.87 (m, 1H), 3,14 was 3.05 (m, 3H), of 2.46 (s, 3H), 2,53-of 2.24 (m, 3H), 1,75-is 1.51 (m, 4H), and 1.63 (d, J=6.8 Hz, 3H), of 1.37 (t, J=7.8 Hz, 3H)

wt.: 482 (M+1)+.

Connection [20]

1H-NMR (CDCl3) δ: for 9.64 (d, J=6,8 Hz, 1H×1/5), to 8.94 (s, 1H×1/5), 8,89 (s, 1H×4/5), 8,80 (d, J=6,8 Hz, 1H×4/5), 8,56 (s, 1H×1/5), charged 8.52 (s, 1H×4/5), 7,43-7,16 (m, 5H), 6,70 of 6.66 (m, 1H), 6,04-6,03 (m,1 H×4/5), 5,85-5,78 (m, 1H×1/5), are 5.36-of 5.26 (m, 1H×1/5), 5,16-5,11 (m, 1H×4/5), 4,34-to 4.33 (m, 1H), 3,10 totaling 3.04 (m, 3H), 2,74-a 2.71 (m, 1H), 2,44-2,17 (m, 2H), and 2.26 (s, 1H×3/5), 2,17 (s, 2H+1H×2/5), 1,90 by 1.68 (m, 4H), of 1.64 (d, J=6,8 Hz, 3H), of 1.37 (t, J=7.8 Hz, 3H)

wt.: 482 (M+1)+.

Example 21

Synthesis of 2-[((1S)-1-{4-[(1S)-2-(tert-butylamino)-1-hydroxyethyl]phenyl}ethyl)amino}-4-[8-(deformity)imidazo[1,2-a]pyridine-3-yl]pyrimidine-5-carbonitrile [21] (hereinafter referred to as compound [21])

29 mg of the hydrochloride specified in the connection header [21] obtained as white solids from 101 mg of the compound [2-5] and 95 mg of compound [4-2] in accordance with the method of example 2-(7).

Spectral data of compound [21] is presented below.

Connection [21]

1H-NMR (DMSO-d6) δ: 10,20 (d, J=6,8 Hz, 1H×1/2), 9,11 (d, J=6,4 Hz, 1H×1/2), 9,06 (d, J=7,2 Hz, 1H×1/2), 8,96 (d, J=8.0 Hz, 1H×1/2), 8,78 (s, 1H×1/2), 8,77 (s, 1H×1/2), a total of 8.74 (s, 1H×1/2), 8,64 (s, 1H×1/2), 7,86 (d, J=8.0 Hz, 1H×1/2), 7,79 (d, J=7,2 Hz, 1H×1/2), 7,51 (t, J=54,4 Hz, 1H×1/2), was 7.45 (t, J=54,4 Hz, 1H×1/2), 7,37-7,29 (m, 5H+1H×1/2), 7,13 (t, J=7.2 Hz, 1H×1/2), and 5.30-5,04 (m, 2H), 4,51 is 4.45 (m, 1H), 2,60-2,50 (m, 2H), 1,54 is 1.48 (m, 3H), and 1.00 (s, 9H×1/2), of 0.93 (s, 9H×1/2),

wt.: 506 (M+1)+.

Example 22

Synthesis of 2-[((1S)-1-{4-[(1S)-2-(tert-butylamino)-1-hydroxyethyl]phenyl}ethyl)amino}-4-[8-chloroimidazo[1,2-a]pyridine-3-yl)pyrimidine-5-carbonitrile [22] (hereinafter referred to as compound [22]).

1.2 g of the hydrochloride specified in the connection header [22] obtained as a white solid from of 2.23 g of compound [2-5] and 2 g of compound [9-1] in accordance with the method of example 2-(7).

Spectral data of compound [22] is presented below.

1H-NMR (DMSO-d6) δ: 10,06 (DD, J=6,8 Hz, 0.8 Hz, 1H×1/2), 9,06 (d, J=6,8 Hz, 1H×1/2), 8,99 (DD, J=7,2 Hz, 1.2 Hz, 1H×1/2), 8,97 (d, J=8,4 Hz, 1H×1/2), 8,78 (s, 1H×1/2), is 8.75 (d, J=5,2 Hz, 1H×1/2), to 8.62 (s, 1H×1/2), 7,79 (DD, J=7,6 Hz, 1.2 Hz, 1H×1/2), 7,72 (DD, J=7,6 Hz, 0.8 Hz, 1H×1/2), 7,37-7,28 (m, 5H+1H×1/2), 7,19 (t, J=7.2 Hz, 1H×1/2), 7,00 (t, J=7.2 Hz, 1H×1/2), 5,28-of 5.05 (m, 2H), 4,49-of 4.44 (m, 1H), 2.57 m) is 2.51 (m, 2H), 1,54 is 1.48 (m, 3H), and 1.00 (s, 9H×1/2), of 0.93 (s, 9H×1/2),

wt.: 490, 492 (M+1)+.

Examples 23 and 24

Synthesis of 4-(8-cyclopropylamino[1,2-a]pyridine-3-yl)-2-[((1S)-1-{4-[[(2S)-1,2-dimethylpyrimidin-2-yl](hydroxy)methyl]phenyl}ethyl)amino]pyrimidine-5-carbonitrile [23] (hereafter, what about the connection [23]and [24] (hereinafter referred to as compound [24]) (here is the link [23] and the compound [24] are diastereomers. Cm. table 6).

(1) To a solution obtained by dissolving 500 mg of H-α-Me-Pro-OH (manufactured by Chem-Impex International Inc.) and 693 mg benzylchloride in 10 ml of 1,4-dioxane and 5 ml of water, was added 1 M aqueous sodium hydroxide solution at room temperature in order to maintain a pH of 10, and the solution was stirred at room temperature for 30 minutes. To the reaction solution was added 5M HCl to bring the pH to 2 and the mixture extracted with ethyl acetate. The obtained organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The insoluble matter is filtered off and the filtrate is concentrated under reduced pressure to obtain 842 mg of 1-[(benzyloxy)carbonyl]-2-methyl-L-Proline [23-1] (hereinafter referred to as compound [23-1]).

(2) To a solution obtained by dissolving 840 mg of the compound [23-1] in 16 ml of tetrahydrofuran, add or 4.31 ml of the complex of borane-metilsulfate (2 M solution in tetrahydrofuran) at room temperature and the mixture is boiled in a vessel under reflux for 4 hours. To the reaction solution was added saturated aqueous solution of sodium bicarbonate and the mixture extracted with ethyl acetate. The obtained organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The insoluble matter is filtered off and the filtrate is concentrated under reduced pressure. Obtained the residue purified by chromatography on a column of silica gel (eluent: hexane/ethyl acetate = 100/0 to 60/40) to obtain 498 mg of benzyl(2S)-2-(hydroxymethyl)-2-methylpyrrolidine-1-carboxylate [23-2] (hereinafter referred to as compound [23-2]).

(3) To a solution obtained by dissolving 377 mg of the compound [23-2] and 147 mg of pyridine in 7.5 ml of chloroform, add 673 mg periodinane dessa-Martin at room temperature and the mixture is boiled in a vessel under reflux for 1 hour. To the reaction solution was added saturated aqueous sodium thiosulfate solution and the mixture extracted with chloroform. The obtained organic layer is successively washed with saturated aqueous sodium hydrogen carbonate and saturated brine, and dried over anhydrous sodium sulfate. The insoluble matter is filtered off and the filtrate is concentrated under reduced pressure. The resulting residue is purified by chromatography on a column of silica gel (eluent: hexane/ethyl acetate 100/0 to 60/40) to obtain 346 mg of benzyl(2S)-2-formyl-2-methylpyrrolidine-1-carboxylate [23-3] (hereinafter referred to as compound [23-3]).

(4) 423 mg of the compound [1-1] and 508 mg of N,N,N',N'-tetramethylethylenediamine dissolved in 22 ml of tetrahydrofuran, the temperature of the solution is maintained at the level 78º and then to it add 1,09 ml n-utility (2,66 M hexane solution). After stirring at the same temperature for 1 hour to obtain the resulting white suspension there was added 2.2 ml of a solution of tetrahydrofuran obtained by dissolving 384 mg of the compound [23-3], and the mixture was stirred at the same temperature for 1.5 hours. The reactions is authorized mixture is added a saturated aqueous solution of ammonium chloride and the mixture extracted with ethyl acetate. The obtained organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. Then the insoluble matter is filtered off and the filtrate is concentrated under reduced pressure to obtain benzyl(2S)-2-[(4-{(1S)-1-[(tert-butoxycarbonyl)amino]ethyl}phenyl)(hydroxy)methyl]-2-methylpyrrolidine-1-carboxylate [23-4]. The compound obtained [23-4] represents the mixture of two isomers, which is then purified by chromatography on a column of silica gel (eluent: hexane/ethyl acetate = 100/0 to 60/40) to obtain 199 mg compounds with low polarity (which was the first eluted in the above conditions) [23-4A], hereinafter referred to as compound [23-4A], and 117 mg of the compound of high polarity (the compound that eluted after that in the above conditions) [23-4b], hereinafter referred to as compound [23-4b]. Here is the link [23-4A] is a precursor compounds [23]and the compound [23-4b] is a precursor compounds [24], described below.

(5) a 23.3 mg of the compound [23] obtained as white solids from 38 mg of the compound [12-1] and 57.5 mg of the compound [23-4-and] in accordance with the methods of examples 17 and 18-((2)-(4).

Spectral data of compound [23] is presented below.

1H-NMR (CDCl3) δ: 9,70-9,62 (m, 1H 1/5), 8,98 (d, J=6,8 Hz, 1H 4/5), of 8.92 (s, 1H 1/5), 8,88 (s, 1H 4/5), to 8.57 (s, 1H 1/5), charged 8.52 (s, 1H 4/5), was 7.36-7,28 (m, 4H), of 6.96-to 6.88 (m, 1H+1H 1/5), of 6.71 of 6.68 (m, 1H 4/5), 5,38 at 5.27 (m, 1H 1/5), 5,15-5,13 (m, 1H 45), 4,39 (s, 1H), 3,10-of 3.07 (m, 1H), 2,59 at 2.45 (m, 2H), 2,19-2,03 (m, 2H), 2,10 (s, 3H), 1,73-is 1.51 (m, 2H), 1,62 (d, J=6.8 Hz, 3H), 1,31-of 1.26 (m, 1H), 1,17-of 1.15 (m, 2H), 0,92 is 0.86 (m, 5H)

wt.: 508 (M+1)+.

(6) to 10.6 mg specified in the connection header [24] obtained as white solids from 38 mg of the compound [12-1] and 57.5 mg of the compound [24-4b] in accordance with the methods of examples 17 and 18-((2)-(4).

Spectral data of compound [24] is presented below.

1H-NMR (CDCl3) δ: 9,63-9,56 (m, 1H 1/5), 8,97 (s, 1H 1/5), of 8.90 (s, 1H 4/5), a total of 8.74 (d, J=6,8 Hz, 1H 4/5), 8,58 (s, 1H 1/5), 8,53 (s, 1H 4/5), 7,44-7,28 (m, 4H), 6,93-6,85 (m, 1H+1H 1/5), 6,68-only 6.64 (m, 1H 4/5), 6,04-of 6.02 (m, 1H 4/5), 5,85-5,80 (m, 1H 1/5), 5,40 is 5.28 (m, 1H 1/5), 5,14-5,11 (m, 1H 4/5), 4,43 (s, 1H), 3,15-3,10 (m, 1H), 2,62-2,49 (m, 2H), 2,28 (s, 3H), 2,13-2,05 (m, 1H), 1,78 of 1.50 (m, 2H), 1,62 (d, J=6.8 Hz, 3H), 1,38-1,25 (m, 1H), 1,15-1,12 (m, 2H), 0,94-0,85 (m, 5H)

wt.: 508 (M+1)+.

Examples 25 and 26

Synthesis of 4-(8-cyclopropylamino[1,2-a]pyridine-3-yl)-2-[((1S)-1-{4-[(R)-[(2R)-1,2-dimethylpyrimidin-2-yl](hydroxy)methyl]phenyl}ethyl)amino]pyrimidine-5-carbonitrile [25] (hereinafter referred to as compound [25]) and 4-(8-cyclopropylamino[1,2-a]pyridine-3-yl)-2-[((1S)-1-{4-[(S)-[(2R)-1,2-dimethylpyrimidin-2-yl](hydroxy)methyl]phenyl}ethyl)amino]pyrimidine-5-carbonitrile [26] (hereinafter referred to as compound [26]) (here is the link [25] and the compound [26] are diastereomers. Cm. table 12).

(1) Benzyl-(2R)-2-[(4-{(1S)-1-[(tert-butoxycarbonyl)amino]ethyl}phenyl)(hydroxy)methyl]-2-methylpyrrolidine-1-carboxylate [25-1] is obtained from 1 g of H-α-Me-D-Pro-OH (manufactured by Chem-Ipex International Inc.) in accordance with the methods of examples 23 and 24(1)-(4). The compound obtained [25-1] was a mixture of the two isomers, and 195 mg [25-1A] (hereinafter referred to as compound [25-1A]) and 134 mg [25-1b] (hereinafter referred to as compound [25-1b]) get in the cleaning conditions described in examples 23 and 24(4). In the examples, the compound of low polarity (compound, which eluted first in the above conditions) represents the connection [25-1A], and the connection with high polarity (the compound that eluted after that in the above conditions) represents the connection [25-1b].

(2) 140 mg of tert-butyl((1S)-1-{4-[(R)-[(2R)-1,2-dimethylpyrimidin-2-yl](hydroxy)methyl]phenyl}ethyl)carbamate [25-2] (hereinafter referred to as compound [25-2]) is obtained from 193 mg of the compound [25-1A] in accordance with the methods of examples 19 and 20(1).

(3) to 21.4 mg specified in the connection header [25] (hereinafter referred to as compound [25]) are obtained as a pale-yellow solid from of 45.6 mg of the compound [12-1] and 49 mg of compound [25-2] in accordance with the method of example 1-(7).

The spectral data of the compound [25] is presented below.

1H-NMR (CDCl3) δ: 9,63-of 9.55 (m, 1H 1/5), 8,97 (s, 1H 1/5), 8,89 (s, 1H 4/5), 8,73 (d, J=6,8 Hz, 1H 4/5), 8,58 (s, 1H 1/5), 8,53 (s, 1H 4/5), 7,37-7,29 (m, 4H), 6,93-6,84 (m, 1H+1H 1/5), 6,68-of 6.65 (m, 1H 4/5), 6,02-6,00 (m, 1H 4/5), of 5.84 is 5.77 (m, 1H 1/5), 5,38-of 5.26 (m, 1H 1/5), 5,13-5,09 (m, 1H 4/5), 4,67 ñ 4.50 (m, 1H), 4,34 (s, 1H), 3,11-of 3.07 (m, 1H), 2,62 at 2.45 (m, 2H), 2,17-2,11 (m, 2H), 2,04 (s, 3H), 1,74-to 1.61 (m, 2H), 1,62 (d, J=6.8 Hz, 3H), 1,32-1,20 (m, 2H), 1,15-1,12 (m, 1H), 0,90-0,85 (m, 5H)

wt.: 508 (M+1)+ .

(4) Absolute configuration specified in the connection header [25] determined in the following way. It is 9.2 mg of the compound [25-1A] add an aqueous solution of potassium hydroxide at room temperature and the mixture was stirred at the same temperature for 2 hours. The reaction solution is concentrated under reduced pressure. To the resulting residue, water is added and the mixture extracted with chloroform. The obtained organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The insoluble matter is filtered off and the filtrate is concentrated under reduced pressure. The resulting residue is purified preparative thin-layer chromatography to obtain 6,1 mg of tert-butyl((1S)-1-{4-[(1R,7aR)-7a-methyl-3-octatetraene-1H-pyrrole[1,2-a][1,3]oxazol-1-yl]phenyl}ethyl)carbamate [25-4] (hereinafter referred to as compound [25-4]. By measuring the NOE (nuclear Overhauser effect) connection [25-4] determine the absolute configuration of compound [25-4] and are specified in the connection header [25].

(5) a 15.7 mg specified in the connection header [26] (hereinafter referred to as compound [26]) are obtained as a pale-yellow solid from of 45.6 mg of the compound [12-1] and 132 mg of the compound [25-1b] in accordance with the methods of examples 25 and 26(2) and (3).

Spectral data of compound [26] is presented below.

1H-NMR (CDCl3) δ: 9,63-of 9.55 (m, 1H 1/5), 8,97-of 8.90 (m, 1H+1H 4/5), 8,58 (who, 1H 1/5), 8,53 (s, 1H 4/5), 7,43-to 7.32 (m, 4H), 6,93-6,85 (m, 1H+1H 1/5), 6,66-6,62 (m, 1H 4/5), 6,04-6,03 (m, 1H 4/5), 5,85-5,78 (m, 1H 1/5), 5,38 is 5.28 (m, 1H 1/5), 5,16-5,13 (m, 1H 4/5), 4,80-of 4.67 (m, 1H), 4,43 (s, 1H), 3.15 and-of 3.07 (m, 1H), 2,63-2,49 (m, 2H), and 2.27 (s, 3H), 2,09-2,05 (m, 1H), 1.85 to 1,50 (m, 2H), 1,62 (d, J=6.8 Hz, 3H), 1,36-of 1.26 (m, 2H), 1,16-to 1.14 (m, 1H), 0,90-0,80 (m, 5H)

wt.: 508 (M+1)+.

(6) Absolute configuration specified in the connection header [26] define the following way. 11.6 mg of tert-butyl((1S)-1-{4-[(1S,7aR)-7a-methyl-3-exoterica-1H-pyrrole[1,2-c][1,3]oxazol-1-yl]phenyl}ethyl)carbamate [25-6] (hereinafter referred to as compound [25-6]) obtained from 30 mg of the compound [25-1b] in accordance with the methods of examples 65 and 66-(4). By measuring the NOE (nuclear Overhauser effect) connection [25-6] determine the absolute configuration of compound [25-6] and are specified in the connection header [26].

Example 27

Synthesis of (1S)-2-(tert-butylamino)-1-[4-((1S)-1-{[4-(8-chloroimidazo[1,2-a]pyridine-3-yl)-5-ftorpirimidinu-2-yl]amino}ethyl)phenyl]ethanol [27] (hereinafter referred to as compound [27])

(1) a Mixture of 18.9 g of 2,4-dichloro-5-ftorpirimidinu (manufactured Fluorochem Co. Ltd), 42.9 g of CIS-1-ethoxy-2-tri-n-butylstannane (synthesized by the method described in J. Am. Chem. Soc., 1977, 99, 7365), 3,97 g dichlorobis(triphenylphosphine)palladium (II) and 380 ml of acetonitrile is stirred at 80 ° C for 3 hours. After cooling, the reaction mixture there was added 113 ml of water and 53 grams of potassium fluoride and the mixture is stirred over night at room temperature. Technology Department is workie substances filtered through celite and the filtrate is extracted with ethyl acetate. The obtained organic layer is successively washed with water and saturated brine and dried over anhydrous sodium sulfate. The insoluble matter is filtered off and the filtrate is concentrated under reduced pressure. Then the obtained residue is purified by chromatography on a column of silica gel (eluent: hexane/ethyl acetate = 100/0 to 40/60) to obtain 14.0 g of 2-chloro-4-[(Z)-2-ethoxyphenyl]-5-ftorpirimidinu [27-1] (hereinafter referred to as compound [27-1]) as a yellow solid.

(2) of 25.2 g of compound [27-1] was dissolved in a mixed solvent of 320 ml of 1,4-dioxane and 32 ml of water. Then add 22,2 g imide N-bromantane acid in conditions of ice cooling and the mixture is stirred at room temperature for 2 hours. To the reaction solution was added 16.0 g of 2-amino-3-chloropyridine, and the mixture is stirred over night at room temperature. Added a saturated aqueous solution of sodium bicarbonate and the mixture extracted with a mixed solvent of chloroform and methanol (mixing ratio: 9/1). The resulting organic layer is dried over anhydrous sodium sulfate. The insoluble matter is filtered off and the filtrate is concentrated under reduced pressure. To the obtained residue, add hexane and the mixture is stirred for 30 minutes. The solid is collected by filtration and dried under reduced pressure DL the receipt of 20.0 g of 8-chloro-3-(2-chloro-5-ftorpirimidinu-4-yl)imidazo[1,2-a]pyridine [27-2] (hereinafter referred to as compound [27-2]) as a yellow solid.

(3) to 15.8 g of compound [2-5] are dissolved in 50 ml of chloroform, is added 45 ml of trichloroacetic acid in conditions of ice cooling and the mixture is stirred at room temperature for 1 hour. The reaction solution is concentrated under reduced pressure and the resulting residue purified by chromatography on a column of silica gel (eluent: chloroform/methanol = 100/0 to 90/10) to obtain 10.7 g of (1S)-1-{4-[(1S)-1-amino-ethyl]phenyl}-2-(tert-butylamino)ethanol [27-3] (hereinafter referred to as compound [27-3]) in the form of a white solid.

(4) a Mixture of 3.00 g of compound [27-2], 3,01 g connection [27-3], 1.12 sodium carbonate and 10 ml of N-methyl-2-pyrrolidinone stirred at 170º within 2 hours. To the reaction solution was added water and the mixture is extracted with a mixed solvent of chloroform and ethyl acetate (mixing ratio: 1/10). The obtained organic layer was washed with water and then dried over anhydrous sodium sulfate. The insoluble matter is filtered and the filtrate concentrated under reduced pressure. The resulting residue is purified by chromatography on a column of silica gel (eluent: chloroform/methanol = 100/0 to 98/2). The resulting solution was concentrated under reduced pressure and the residue is dissolved in ethyl acetate and utverjdayut to get 3,79 g specified in the connection header [27] in the form of a pale yellow solid.

Spectral data with the unity [27] is presented below.

1H-NMR (CDCl3) δ: which 9.22 (users, 1H), to 8.41 (d, J=3,9 Hz, 1H), 8,24 (d, J=3,9 Hz, 1H), 7,42-7,37 (m, 5H), 6,68 (users, 1H), 5,50 (d, J=5,9 Hz, 1H), 5,03 (Quint., J=6,8 Hz, 1H), 4,57 (DD, J=9,0 Hz and 3.7 Hz, 1H), 2,87 (DD, 12.0 Hz, and 3.7 Hz, 1H), 2,53 (DD, J=12.0 Hz, 9.0 Hz, 1H), 1,60 (d, J=6.8 Hz, 3H), of 1.07 (s, 9H)

wt.: 483 (M+1)+.

Example 28

Synthesis of (1S)-1-[4-((1S)-1-{[4-(8-chloroimidazo[1,2-a]pyridine-3-yl)-5-ftorpirimidinu-2-yl]amino}ethyl)phenyl]-2-[(1-methylcyclopentene)amino]ethanol [28] (hereinafter referred to as compound [28])

(1) a Mixture of 500 mg of the compound [2-4], 639 mg monohydrochloride 1-methylcyclopentadiene (synthesized by the method described in J. Med. Chem., 2006, 49, 3068), 613 mg N,N-diisopropylethylamine, 5 ml ethanol and 5 ml of water is boiled in a vessel with reflux condenser. The reaction solution concentrate. To the resulting residue, water is added and the mixture extracted with ethyl acetate. The obtained organic layer was washed with water and then dried over anhydrous sodium sulfate. The insoluble matter is filtered and the filtrate concentrated under reduced pressure. The resulting residue is purified by chromatography on a column of silica gel (eluent: chloroform/methanol = 100/0 to 95/5) to obtain 365 mg of tert-butyl[((1S)-1-{4-[(1S)-1-hydroxy-2-[(1-methylcyclopentene)amino]ethyl}phenyl)ethyl]carbamate [28-1] (hereinafter referred to as compound [28-1]) in the form of a white solid substance).

(2) of 25.9 mg specified in the connection header [28] (hereinafter referred to as compound [28]) recip which are in the form of a pale yellow solid from 45 mg of compound [27-2] and 150 mg of compound [28-1] in accordance with the methods of example 27-(3) and (4).

The spectral data of the compound [28] is presented below.

1H-NMR (CDCl3) δ: of 9.21 (user., 1H), to 8.41 (d, J=3,9 Hz, 1H), 8,23 (d, J=3,4 Hz, 1H), 7,42-7,37 (m, 5H), 7,26 (s, 1H), 6,68 (users, 1H), 5,54 (users, 1H), 5,07-4,99 (m, 1H), 4,58 (DD, J=3,9 Hz, 9.3 Hz, 1H), 2,88 (DD, J=3,9 Hz and 12.2 Hz, 1H), 2,53 (DD, J=9,3 Hz and 12.2 Hz, 1H), 1,65-of 1.52 (m, 6H), 1,60 (d, J=6.8 Hz, 3H), 1,47-of 1.39 (m, 2H), 1.30 and of 1.27 (m, 1H), 1,12 (s, 3H)

wt.: 509, 511 (M+1)+.

Example 29

Synthesis of (1S)-2-(tert-butylamino)-1-[4-((1S)-1-({4-(8-cyclopropylamino[1,2-a]pyridine-3-yl)-5-methylpyrimidin-2-yl]amino)ethyl)phenyl]ethanol [29] (hereinafter referred to as compound [29]).

(1) to 23.1 mg of 3-(2-chloro-5-methylpyrimidin-4-yl)-8-cyclopropylamino[1,2-a]pyridine [29-1] (hereinafter referred to as compound [29-1]) is obtained from 139 mg of 2,4-dichloro-5-methylpyrimidine (manufactured by Aldrich Corporation) and 50.2 mg of 3-cyclopropylmethyl-2-amine (synthesized by the method described on page 142 International publication WO 2006/025567), in accordance with the methods of example 27-(1) and (2).

(2) 10,9 mg specified in the connection header [29] (hereinafter referred to as compound [29]) are obtained in the form of a solid white color of 53 mg of the compound [27-3] and 21.3 mg of the compound [29-1] in accordance with the method of example 27-(4).

Spectral data of compound [29] is presented below.

1H-NMR (CDCl3) δ: 8,77 (users, 1H), 8,21 (s, 1H), of 8.06 (s, 1H), 7,38 (s, 4H), 6,77 (d, J=6,8 Hz, 1H), 6,54 (users, 1H), 5,38 (d, J=5,9 Hz, 1H), 5,11 (Quint., J=7,0 Hz, 1H), 4,60 (DD, J=9,0 Hz and 3.7 Hz, 1H), 2,89 (DD, J=11.7 Hz, 3.4 G is, 1H), 2,64-of 2.56 (m, 2H), 2,35 (s, 3H), and 1.56 (d, J=6.8 Hz, 3H), 1,15-1,10 (m, 2H), only 1.08 (s, 9H), 0,92-of 0.82 (m, 2H)

wt.: 485 (M+1)+.

Example 30

Synthesis of (1S)-2-(tert-butylamino)-1-[4-((1S)-1-{[4-(8-cyclopropylamino[1,2-a]pyridine-3-yl)-5-ftorpirimidinu-2-yl]amino}ethyl)phenyl]ethanol [30] (hereinafter referred to as compound [30]).

(1) to 13.4 mg of 3-(2-chloro-5-ftorpirimidinu-4-yl)-8-cyclopropylamino[1,2-a]pyridine [30-1] (hereinafter referred to as compound [30-1]) is obtained from the 11.5 g of 2,4-dichloro-5-ftorpirimidinu (manufactured by Fluorochem Co. Ltd.) and of 9.21 mg 3-cyclopropylamino-2-amine (synthesized by the method described on page 142 International publication WO 2006/025567) in accordance with the methods of example 27-(1) and (2).

(2) 673 mg specified in the connection header [30] (hereinafter referred to as compound [30]) are obtained as orange solids from 1,17 g connection [27-3] and 1.1 g of compound [30-1] in accordance with the method of example 27-(4).

Spectral data of compound [30] is presented below.

1H-NMR (CDCl3) δ: 9,20 (users, 1H), to 8.41 (d, J=3,9 Hz, 1H), 8,19 (d, J=3,9 Hz, 1H), 7,39 (square, 4H), 6,83 (d, J=6,8 Hz, 1H), 6,69 (m, 1H), 5,44 (d, J=5,9 Hz, 1H), 5,06 (Quint., J=7,3 Hz, 1H), 4,57 (DD, J=8,8 Hz, 3.4 Hz, 1H), 2,85 (DD, 12.0 Hz, and 3.7 Hz, 1H), 2,62 (DD, J=11.7 Hz, 8,8 Hz, 1H), 1,59 (d, J=6.8 Hz, 3H), of 1.13 (d, J=8,8 Hz, 2H), 1.06 a (s, 9H), 0.87 (m, 2H)

wt.: 489 (M+1)+.

Example 31

Synthesis of (1S)-2-(tert-butylamino)-1-{4-[(1S)-1-({5-fluoro-4-(8-(trifluoromethyl)imidazo[1,2-a]pyridine-3-yl]pyrimidine-2-yl}amino)ethyl]phenyl}ethanol [31](hereinafter referred to as compound [31]).

(1) 143 mg of 3-(2-chloro-5-ftorpirimidinu-4-yl)-8-(trifluoromethyl)imidazo[1,2-a]pyridine [31-1] (hereinafter referred to as compound [31-1]) is obtained from 113 mg of 2,4-dichloro-5-ftorpirimidinu (manufactured by Fluorochem Co. Ltd.) and 104 mg of 3-triptorelin-2-amine (synthesized by the method described on page 81 International publication WO 2006/025567) in accordance with the methods of example 27-(1) and (2).

(2) of 30.6 mg specified in the connection header [31] (hereinafter referred to as compound [31]) are obtained as a pale-yellow solid from of 45.6 mg of the compound [27-3] and 47 mg of the compound [31-1] in accordance with the method of example 27-(4).

Spectral data of compound [31] is presented below.

1H-NMR (CDCl3) δ: of 9.55-a 9.25 (m, 1H), of 8.47 (d, J=3,9 Hz, 1H), compared to 8.26 (d, J=3,9 Hz, 1H), to 7.64 (d, J=7,3 Hz, 1H), 7,43-7,37 (m, 4H), 6,85-of 6.73 (m, 1H), 5,55-of 5.53 (m, 1H), 5,04-free 5.01 (m, 1H), 4,59-4,56 (m, 1H), 2,87 (DD, 12.0 Hz, the 3.7 Hz, 1H), 2,53 (DD, J=12.0 Hz, 8,8 Hz, 1H), 1,61 (d, J=6.8 Hz, 3H), of 1.07 (s, 9H)

wt.: 517 (M+1)+.

Example 32

Synthesis of (R)-[4-((1S)-1-{[4-(8-chloroimidazo[1,2-a]pyridine-3-yl)-5-ftorpirimidinu-2-yl]amino}ethyl)phenyl][(2R)-1,2-dimethylpyrimidin-2-yl]methanol [32] (hereinafter referred to as compound [32]).

15.6 mg specified in the connection header [32] (hereinafter referred to as compound [32]) obtained as yellow solid from 34,2 mg of the compound [25-4] and 30 mg of compound [27-2] in accordance with the methods of example 27-(3) and (4).

Spectral data of compound [32] below

1H-NMR (CDCl3) δ: 9,27-9,05 (m, 1H), 8,39 (d, J=3,9 Hz, 1H), 8,24 (d, J=3,9 Hz, 1H), 7,42-7,30 (m, 5H), 6,78-6,70 (m, 1H), 5,01-4,99 (m, 1H), 4,36 (s, 1H), 3,11-of 3.07 (m, 1H), 2,52 is 2.46 (m, 1H), and 2.26 (s, 3H), of 2.09 (s, 3H), a 1.75-of 1.53 (m, 2H), 1,60 (d, J=6.8 Hz, 3H), 1,25-to 1.21 (m, 1H), 0,86 (s, 3H)

wt.: 495, 497 (M+1)+.

Example 33

Synthesis of [4-((1S)-1-{[4-(8-chloroimidazo[1,2-a]pyridine-3-yl)-5-ftorpirimidinu-2-yl]amino}ethyl)phenyl][(2S)-1,2-dimethylpyrimidin-2-yl]methanol [33] (hereinafter referred to as the compound [33]).

(1) 1,69 g of tert-butyl((1S)-1-{4-[[(2S)-1,2-dimethylpyrimidin-2-yl)(hydroxy)methyl]phenyl}ethyl)carbamate [33-1] (hereinafter referred to as compound [33-1]) is obtained from 2,55 g connection [23-4A] in accordance with the methods of examples 19 and 20(1).

(2) 10.5 mg specified in the connection header [33] (hereinafter referred to as the compound [33]) is obtained from 30 mg of the compound [33-1] and 18.4 mg of the compound [27-2] in accordance with the methods of example 27-(3) and (4).

The spectral data of the compound [33] is presented below.

1H-NMR (CDCl3) δ: 9,48-a 9.35 (m, 1H), 8,42 (d, J=3,4 Hz, 1H), 8,24 (d, J=3,9 Hz, 1H), 7,42-7,28 (m, 5H), 6,78-6,70 (m, 1H), of 5.05-to 5.03 (m, 1H), 4,37 (s, 1H), 3,12-of 3.07 (m, 1H), of 2.51-2,47 (m, 1H), 2,08 (s, 3H), of 1.85 (s, 3H), 1.85 to 1,71 (m, 3H), of 1.59 (d, J=6.8 Hz, 3H), of 0.85 (s, 3H)

wt.: 495, 497 (M+1)+.

Examples 34 and 35

Synthesis of 1-[4-((1S)-1-{[4-(8-chloroimidazo[1,2-a]pyridine-3-yl)-5-ftorpirimidinu-2-yl]amino}ethyl)phenyl]-2-(dimethylamino)-2-methylpropan-1-ol [34] (hereinafter referred to as compound [34]and [35] (hereinafter referred to as compound [35]) (here is the link [34] and the compound[35] are diastereomers. Cm. table 14)

(1) 51 g of dimethyl sulfoxide was dissolved in 70 ml of dichloromethane and the solution temperature kept at-78º. Then to it add 160 ml of dichloromethane solution in which the dissolved 59,1 g oxalidaceae. The mixture was stirred at the same temperature for 30 minutes and then added to the dichloromethane solution, which is dissolved and 18.2 g of 2-(dimethylamino)-2-methylpropan-1-ol. The mixture was stirred at the same temperature for 20 minutes, there was added 107 g of triethylamine and the mixture was stirred at the same temperature for 40 minutes. The reaction mixture was warmed to room temperature and then diluted with dichloromethane. The obtained organic layer is successively washed with saturated aqueous sodium hydrogen carbonate and saturated brine, and dried over anhydrous magnesium sulfate. Then the insoluble matter is filtered off and the filtrate is concentrated under reduced pressure. The resulting residue is purified by distillation under reduced pressure to obtain 11.1 g of 2-(dimethylamino)-2-methylpropanal [34-1] (hereinafter referred to as compound [34-1]).

(2) 12.8 g of tert-butyl((1S)-1-{4-[2-(dimethylamino)-1-hydroxy-2-methylpropyl]phenyl}ethyl)carbamate [34-2] (hereinafter referred to as compound [34-2]) is obtained from 24,1 g of compound [1-1] and 11.1 g of compound [34-1] in accordance with the methods of examples 23 and 24(4).

(3) 2,31 g of the mixture is shown in the title compounds [34] and [35] derived from 6,24 g connection [34-2] and of 2.34 g of compound [27-2] in accordance with the methods of examples 27(3) and (4).

(4) to 70.2 mg of a mixture of compounds [34] and [35] share on Chiralcel AD-h

Conditions for optical resolution the following.

Column: Chiralcel AD-H (Chiralcel AD-H manufactured by Daicel Chemical Industries, Ltd.), diameter 20 mm and length 250 mm

Eluent: hexane/2-propanol/diethylamine = 75/25/0 .1.

Flow rate: 12 ml/min

The resulting solution was concentrated under reduced pressure to obtain 22,5 mg specified in the connection header [34] (RT=11.5 min) and 21 mg specified in the connection header [34] (RT=22.3 minutes).

Spectral data of compound [34] is presented below.

1H-NMR (CD3OD) δ: of 8.37 (s, 1H), 8,29 (s, 1H), of 7.75 (d, J=7,0 Hz, 1H), 7,51-7,42 (m, 5H), 7,21-7,05 (m, 1H), 5,12-free 5.01 (m, 1H), 4.95 points (s, 1H), equal to 2.94 (s, 3H), 2,80 (s, 3H), 1,58 (d, J=7,0 Hz, 3H), of 1.16 (s, 3H), 1,13 (, 3H)

wt.: 483, 485 (M+1)+.

Spectral data of compound [35] is presented below.

1H-NMR ((CD3OD) δ: scored 8.38 (s, 1H), 8,29 (s, 1H), of 7.75 (d, J=7,0 Hz, 1H), 7,51-the 7.43 (m, 5H), 7,19? 7.04 baby mortality (m, 1H), 5,10-free 5.01 (m, 1H), 4,96 (s, 1H), equal to 2.94 (s, 3H), 2,80 (s, 3H), 1,58 (d, J=7,0 Hz, 3H), of 1.17 (s, 3H), 1,12 (, 3H)

wt.: 483, 485 (M+1)+.

Examples 36 and 37

Synthesis of [4-((1S)-1-{[4-(8-chloroimidazo[1,2-a]pyridine-3-yl)-5-ftorpirimidinu-2-yl]amino}ethyl)phenyl](1-isopropylpyridine-3-yl)methanol [36] (hereinafter referred to as compound [36]and [37] (hereinafter referred to as compound [37]) (here is the link [36] and the compound [37] are diastereomers. Cm. table 15).

(1) 9,94 g of tert-butyl[(1S)-1-(4-{[1-(diphenylmethyl)azetidin-3-yl]carbonyl}phenyl)ethyl]carbamate [361] (hereinafter referred to as compound [36-1]) is obtained from 1-benzhydrylamine-3-carboxylic acid, in accordance with the methods of example 1-(1) and (2).

(2) 9,94 g connection [36-1] dissolved in 100 ml of tetrahydrofuran and 20 ml of methanol, to it add 799 mg of sodium borohydride at room temperature and the mixture was stirred at the same temperature for 2.5 hours. To the reaction mixture, water is added and the mixture extracted with chloroform. The resulting organic layer is dried over anhydrous sodium sulfate. Then the insoluble matter is filtered off and the filtrate is concentrated under reduced pressure. The resulting residue is purified by chromatography on a column of silica gel (eluent: hexane/ethyl acetate = 100/0 to 30/70) to obtain 632 mg of tert-butyl((1S)-1-{4-[[1-(diphenylmethyl)azetidin-3-yl](hydroxy)methyl]phenyl}ethyl)carbamate [36-2] (hereinafter referred to as compound [36-2]).

(3) of 6.26 g of tert-butyl((1S)-1-{4-[hydroxy(1-isopropylpyridine-3-yl)methyl]phenyl}ethyl)carbamate [36-3] (hereinafter referred to as compound [36-3]) is obtained from 9,79 g connection [36-2] in accordance with the methods of example 11-(3) and (4).

(4) 135 mg of the mixture specified in the title compounds [36] and [37] obtained from 720 mg of the compound [36-3] and 200 mg of the compound [27-2] in accordance with the methods of example 27-(3) and (4).

(5) 135 mg of a mixture of compounds [36] and [37] share on Chiralcel AD-h

The optical separation conditions are as follows.

Column: Chiralcel AD-H (Chiralcel AD-H manufactured by Daicel Chemical Industries, Ltd.), diameter 20 mm, length 250 mm

Eluent: hexa is/ethanol/diethylamine = 70/30/1.

Flow rate: 12 ml/min

The resulting solution was concentrated under reduced pressure to obtain 36 mg specified in the connection header [36] (RT = 11.4 min) and 63 mg of the title compound [37] (RT = 21,8 minutes).

Spectral data of compound [36] is presented below.

1H-NMR (CDCl3) δ: 8,90 (user., 1H), they were 8.22-8,16 (m, 2H), 7,43-7,38 (m, 4H), 7,32 (d, J=7,3 Hz, 1H), 7,27 (s, 1H), 6,60 (users, 1H), 5,58 (users, 1H), 4.95 points (users, 1H), 4,89 (d, J=6,8 Hz, 1H), up 3.22 (d, J=5,9 Hz, 2H), 3,15-of 3.12 (m, 1H), 3,05 totaling 3.04 (m, 1H), 2,68-to 2.65 (m, 1H), 2,30 was 2.25 (m, 1H)

wt.: 495, 497 (M+1)+.

Spectral data of compound [37] is presented below.

1H-NMR (CDCl3) δ: 8,99 (user., 1H), 8,29 (users, 1H), 8,18-8,17 (m, 1H), 7,41-7,37 (m, 4H), 7,32 (d, J=6,8 Hz, 1H), 7,27 (s, 1H), 6,57 (user., 1H), 5,61 (user., 1H), 4,99-of 4.95 (m, 1H), 4,87 (d, J=6.3 Hz, 1H), 3,21 (d, J=6.3 Hz, 2H), 3,14-3,10 (m, 1H), 3,05-to 3.02 (m, 1H), 2,66-2,62 (m, 1H), and 2.27 (Quint., J=6.3 Hz, 1H), 1,58 (d, J=6.8 Hz, 3H), 0,89 (d, J=5,9 Hz, 6H)

wt.: 495, 497 (M+1)+.

Examples 38

Synthesis of (1S)-2-tert-butylamino)-1-{4-[(1S)-1-({4-[8-(deformity)imidazo[1,2-a]pyridine-3-yl]-5-ftorpirimidinu-2-yl}amino)ethyl]phenyl}ethanol [38] (hereinafter referred to as compound [38]).

(1) 180 mg of 3-(2-chloro-5-ftorpirimidinu-4-yl)imidazo[1,2-a]pyridine-8-carbaldehyde [38-1] (hereinafter referred to as compound [38-1]) is obtained from 568 mg of 2,4-dichloro-5-ftorpirimidinu (manufactured Fluorochem Co. Ltd) and 415 mg of 2-aminonicotinamide (manufactured by Aldrich Corporation) in accordance with the methods of example 27-(1) and (2).

(2) 97 mg of 3-(2-chloro-5-f is birimizin-4-yl)-8-(deformity)imidazo[1,2-a]pyridine [38-2] (hereinafter referred to as compound [38-2]) is obtained from 180 mg of the compound [38-1] in accordance with the method of example 4-(2).

(3) 12.9 mg specified in the connection header [38] (hereinafter referred to as compound [38]) is obtained from a 33.5 mg of the compound [27-3] and 30 mg of compound [38-2] in accordance with example 27-(4).

Spectral data of compound [38] is presented below.

1H-NMR (CDCl3) δ: 9,36 (users, 1H), 8,43-to 8.40 (m, 1H 4/5), 8,25 is 8.22 (m, 1H 4/5), 7,97-to 7.93 (m, 1H 1/5+1H 1/5), 7,63-7,58 (m, 1H 4/5), 7,50-7,37 (m, 4H+1H 1/5+1H 1/5), 7,32 (t, J=55,1 Hz, 1H), 6.87 in-6,79 (m, 1H 4/5), 5,57-the 5.51 (m, 1H 4/5), 5,06-5,00 (m, 1H 4/5), 4,67-of 4.57 (m, 1H 4/5+1H 1/5+1H 1/5), 4,32-4.26 deaths (m, 1H 1/5), 2,98-only 2.91 (m, 1H 1/5), 2,90-2,84 (m, 1H 4/5), 2,59 is 2.51 (m, 1H), 1,62 is 1.58 (m, 3H), 1,12-of 1.10 (m, 9H 1/5), 1,09 was 1.06 (m, 9H 4/5)

wt.: 499 (M+1)+.

Link 1

Synthesis of tert-butyl[(1S)-1-(4-formylphenyl)ethyl]carbamate [39]

5 g of the compound [1-1] dissolved in 100 ml of tetrahydrofuran and cooled to-78º. Then to it add to 31.2 ml of n-utility (1,6M solution of hexane) and the mixture is stirred for 1 hour at the same temperature. To the resulting white suspension add 774 μl of N,N-dimethylformamide, stirred for 5 hours while gradually heating up again to room temperature. To the reaction mixture is added saturated aqueous solution of ammonium chloride and the mixture extracted with ethyl acetate. The obtained organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The insoluble matter is filtered off, the filtrate is concentrated under reduced pressure and the resulting residue purified chromate what graphy on a column of silica gel (eluent: hexane/ethyl acetate = 100/0-50/50) to obtain 514 mg of tert-butyl[(1S)-1-(4-formylphenyl)ethyl]carbamate [39] in the form of a pale yellow amorphous substance.

Link 2

Synthesis of benzyl-4-[(4-{(1S)-1-[(tert-butoxycarbonyl)amino]ethyl}phenyl)(hydroxy)methyl]piperidine-1-carboxylate [40].

267 mg of the compound [42] (see reference 4) dissolved in a mixed solvent of 10 ml of tetrahydrofuran and 1 ml of methanol, then added 22 mg sodium borohydride and the mixture is stirred over night at room temperature. Water added to the reaction solution, extracted with ethyl acetate. The obtained organic layer was washed with water and saturated brine in that order and dried over anhydrous magnesium sulfate. The insoluble matter is filtered off, the filtrate is concentrated under reduced pressure and the resulting residue purified by chromatography on a column of silica gel (eluent: hexane/ethyl acetate = 100/0-30/70) to obtain 256 mg of benzyl-4-[(4-{(1S)-1-[(tert-butoxycarbonyl)amino]ethyl}phenyl)(hydroxy)methyl]piperidine-1-carboxylate [40].

Link 3

Synthesis of benzyl-(2R)-2-[(4-{(1S)-1-[(tert-butoxycarbonyl)amino]ethyl}phenyl)(hydroxy)methyl]piperidine-1-carboxylate [41].

337 mg of benzyl-(2R)-2-[(4-{(1S)-1-[(tert-butoxycarbonyl)amino]ethyl}phenyl)(hydroxy)methyl]piperidine-1-carboxylate [41] obtained from 1.06 g benzyl-(2R)-2-formylpyridine-1-carboxylate (synthesized according to the method described in the document Bioorg. Med. Chem. 2003, 11, 3153-3164) and 1.14 g of the compound [1-1] in accordance with the method of the example is 2-(1).

Link 4

Synthesis of benzyl-4-(4-{(1S)-1-[(tert-butoxycarbonyl)amino]ethyl}benzoyl)piperidine-1-carboxylate [42].

1.26 g benzyl-4-(4-{(1S)-1-[(tert-butoxycarbonyl)amino]ethyl}benzoyl)piperidine-1-carboxylate [42] obtained from 2,39 g benzyl-4-(N-methoxy-N-methylcarbamoyl)piperidine-1-carboxylate and 2.13 g of compound [1-1] in accordance with the method of example 2-(1).

Industrial applicability

The compound of the present invention has a pronounced inhibitory effect against PLK1 and cell proliferation and thus it is expected that it can serve as a useful anti-cancer agents in medicine.

1. The compound of the formula [1]:

or its pharmaceutically acceptable salt, possibly in the form of (1S)-isomers, where:
R1represents a halogen atom; the group of lower alkyl having 1-2 carbon atoms which may be substituted by 1-3 fluorine atoms; or cyclopropyl group;
R2represents a hydrogen atom;
one of R3and R4represents a hydrogen atom while the other one of R3and R4is:
a) the group of lower alkyl, substituted NRaRbwhere each Raand Rbthat may be the same or different, represent a group of lower alkyl, or each Raand Rbthat may be different to depict ablaut a hydrogen atom, the group of lower alkyl or cycloalkyl group having 3-6 carbon atoms, where cycloalkyl group may be substituted by one or more substituents, which may be the same or different, selected from the following compounds according to claim 1):
1) the group of lower alkyl;
b) 4-6-membered aliphatic heterocyclic group selected from azetidine group, pyrrolidinyl group and piperidinyloxy group;
c) the group of lower alkyl, substituted 4-6-membered aliphatic heterocyclic group selected from azetidine group, pyrrolidinyl group and piperidinyloxy group;
d) a 6-membered aromatic heterocyclic group selected from peredelnoj group;
where each of the aliphatic heterocyclic group and aromatic heterocyclic group independently may be substituted by one or more substituents, which may be the same or different, selected from the following compounds according to claim 1):
1) the group of lower alkyl;
R5represents a hydrogen atom, a cyano, a halogen atom or a group of the lower alkyl.

2. The compound according to claim 1 or its pharmaceutically acceptable salt, where R5represents a hydrogen atom, a cyano, a halogen atom or a metal group.

3. The compound according to claim 2 or its pharmaceutically acceptable salt, where R1is gruppensex of alkyl, having 1-2 carbon atoms which may be substituted by 1-3 fluorine atoms, cyclopropene group or chlorine atom; a R2represents a hydrogen atom.

4. The compound according to claim 1 or its pharmaceutically acceptable salt, where
one of R3and R4represents a hydrogen atom while the other of R3and R4is:
a) the group of lower alkyl, substituted NRaRbwhere each Raand Rbthat may be the same or different, represent a group of lower alkyl, or each Raand Rbthat may be different, represent a hydrogen atom, a group of lower alkyl or cycloalkyl group having 5-6 carbon atoms, where cycloalkyl group may be substituted by one or more substituents, which may be the same or different, selected from the following compounds according to claim 1):
1) the group of lower alkyl; or
b) 4-6-membered aliphatic heterocyclic group selected from azetidine group, pyrrolidinyl group and piperidinyloxy group, aliphatic heterocyclic group may be substituted by one or more substituents, which may be the same Lili different, selected from the following compounds 1):
1) the group is lower alkyl.

5. The compound according to claim 1 or its pharmaceutically acceptable salt, where:
R1performance is made by the group of lower alkyl, having 1-2 carbon atoms which may be substituted by 1-3 fluorine atoms; cyclopropyl group; or a halogen atom;
R2represents a hydrogen atom;
one of R3and R4represents a hydrogen atom while the other of R3and R4represents a group of the lower alkyl (where specified lower alkyl represents a linear or branched alkyl group having 1-3 carbon atoms), which is N-substituted or N,N-di-substituted linear or branched alkyl group having 1-5 carbon atoms; piperidinyl group, which is N-substituted linear or branched alkyl group having 1-5 carbon atoms; pyrrolidinyloxy group, which is N-substituted linear or branched alkyl group having 1-5 carbon atoms; azetidinol group, which is N-substituted linear or branched alkyl group having 1-5 carbon atoms; or cycloalkyl group having 5-6 carbon atoms, where each of piperidinyloxy group, pyrrolidinyl group and azetidine group independently can be, additionally, a substituted linear or branched alkyl group having 1-3 carbon atoms, and cycloalkyl group may be substituted linear or branched alkyl group having 1-3 carbon atoms; and
R5represents a cyano, a halogen atom or a methyl group is at.

6. The compound according to claim 5 or its pharmaceutically acceptable salt, where:
R1represents a metal group, ethyl group, deformational group, triptorelin group, cyclopropyl group or a chlorine atom;
R2represents a hydrogen atom;
one of R3and R4represents a hydrogen atom while the other of R3and R4represents a linear or branched alkyl group having 1-3 carbon atoms, which is substituted by dimethylaminopropoxy, isopropylaminocarbonyl, 1,1-dimethylpropyleneurea, or tert-butylamino; piperidinyloxy group, which is N-substituted linear or branched alkyl group having 1-5 carbon atoms; pyrrolidinyloxy group, which is N-substituted linear or branched alkyl group having 1-5 carbon atoms; azetidinol group, which is N-substituted linear or branched alkyl group having 1-5 carbon atoms; or cyclopentyloxy group which may be substituted by a methyl group, where each of piperidinyloxy group, pyrrolidinyl group and azetidinone group independently may in addition be substituted linear or branched alkyl group having 1-3 carbon atoms; and
R5represents cyano, fluorine atom or methyl group.

7. The compound according to claim 1, which is submitted is:
(a) 2-[((1S)-1-{4-[2-(tert-butylamino)-1-hydroxyethyl]phenyl}ethyl)amino]-4-(8-ethylimidazole[1,2-a]pyridine-3-yl)pyrimidine-5-carbonitrile;
(b) 4-(8-ethylimidazole[1,2-a]pyridine-3-yl)-2-[((1S)-1-{4-[hydroxy(1-isopropylpiperazine-4-yl)methyl]phenyl}ethyl)amino]pyrimidine-5-carbonitrile;
(c) 4-(8-cyclopropylamino[1,2-a]pyridine-3-yl)-2-[((1S)-1-{4-[hydroxy(1-methylpiperidin-4-yl)methyl]phenyl}ethyl)amino]pyrimidine-5-carbonitrile;
(d) 4-(8-ethylimidazole[1,2-a]pyridine-3-yl)-2-[((1S)-1-{4-[hydroxy(1-methylpiperidin-3-yl)methyl]phenyl}ethyl)amino]pyrimidine-5-carbonitrile;
(e) 2-[((1S)-1-{4-[2-(tert-butylamino)-1-hydroxyethyl]phenyl}ethyl)amino]-4-(8-chloroimidazo[1,2-a]pyridine-3-yl)pyrimidine-5-carbonitrile;
(f) 2-[((1S)-1-{4-[2-(tert-butylamino)-1-hydroxyethyl]phenyl}ethyl)amino]-4-[8-deformity)imidazo[1,2-a]pyridine-3-yl)pyrimidine-5-carbonitrile;
(g) 4-(8-cyclopropylamino[1,2-a]pyridine-3-yl)-2-[((1S)-1-{4-[(1,2-dimethylpyridin-2-yl)(hydroxy)methyl]phenyl}ethyl)amino]pyrimidine-5-carbonitrile;
(h) (1S)-2-(tert-butylamino)-1-[4-((1S)-1-{[4-(8-chloroimidazo[1,2-a]pyridine-3-yl)-5-ftorpirimidinu-2-yl]amino}ethyl)phenyl]ethanol;
(i) (1S)-1-[4-((1S)-1-{[4-(8-chloroimidazo[1,2-a]pyridine-3-yl)-5-ftorpirimidinu-2-yl]amino}ethyl)phenyl]-2-[(Methylcyclopentane)amino]ethanol;
(j) (1S)-2-(tert-butylamino)-1-[4-((1S)-1-{[4-(8-cyclopropylamino[1,2-a]pyridine-3-yl)-5-methylpyrimidin-2-yl]amino}ethyl)phenyl]ethanol;
(k) (1S)-2-(tert-butylamino)-1-[4-((1S)-1-{[4-(8-cyclopropylamino[1,2-a]pyridine-3-yl)-5-perperi the one-2-yl]amino}ethyl)phenyl]ethanol;
(l) (1S)-2-(tert-butylamino)-1-{4-[(1S)-1-({5-fluoro-4-[8-(trifluoromethyl)imidazo[1,2-a]pyridine-3-yl]pyrimidine-2-yl}amino)ethyl]phenyl}ethanol;
(m) [4-((1S)-1-{[4-(8-chloroimidazo[1,2-a]pyridine-3-yl)-5-ftorpirimidinu-2-yl]amino}ethyl)phenyl](1,2-dimethylpyridin-2-yl)methanol;
(n) 1-[4-((1S)-1-{[4-(8-chloroimidazo[1,2-a]pyridine-3-yl)-5-ftorpirimidinu-2-yl]amino}ethyl)phenyl]-2-(dimethylamino)-2-methylpropan-1-ol;
(o) [4-((1S)-1-{[4-(8-chloroimidazo[1,2-a]pyridine-3-yl)-5-ftorpirimidinu-2-yl]amino}ethyl)phenyl](1-isopropylpyridine-3-yl)methanol; or
(R) (1S)-2-(tert-butylamino)-1-{4-[(1S)-1-({4-[8-(deformity)imidazo[1,2-a]pyridine-3-yl]-5-ftorpirimidinu-2-yl}amino)ethyl]phenyl}ethanol,
or their pharmaceutically acceptable salt.

8. Pharmaceutical composition for use as an inhibitor of PLK1, which includes, together with a pharmaceutically acceptable carrier or diluent, at least one compound according to claim 1 in an effective amount as an active ingredient.

9. The PLK1 inhibitor containing, together with a pharmaceutically acceptable carrier or diluent, at least one compound according to claim 1 in an effective amount as an active ingredient.

10. Antitumor agent containing, together with a pharmaceutically acceptable carrier or diluent, at least one compound according to claim 1 in an effective amount as an active ingredient.



 

Same patents:

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention refers to organic chemistry, namely new 1H-pyrrolo[3,4-b]quinoline-3,9(2H, 4H)-dione derivatives of general formula 1

wherein R1=Alk, Ar; R2=H, Alk, halogen; R3=H, Alk, halogen; R4=H, Alk, halogen; R5=H, Alk, halogen; R6=CH2Ar, R7=Ar, Also, the invention refers to a method for preparing them.

EFFECT: there are prepared new 1H-pyrrolo[3,4-b]quinoline-3,9(2H, 4H)-dione derivatives possessing anti-tuberculosis activity.

3 cl, 1 tbl, 9 ex

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of formula I , and pharmaceutically acceptable salts thereof, where L denotes O, S, or CH2; Y denotes N or CH; Z denotes CR3; G denotes CH; R1 denotes a heteroaryl ring of formula , where D1 denotes S, O; D2 denotes N or CR12; D3 denotes CR12; R2 denotes (C6-C10)-aryl; 5-9-member mono- or bicyclic heteroaryl with 1 or 2 heteroatoms independently selected from N or S; a saturated or partially saturated (C3-C7)-cycloalkyl; or a saturated 5-6-member heteocyclyl with 1 heteroatom selected from N, where said aryl, heteroaryl, cycloalkyl and heterocyclyl are optionally substituted with one or two groups independently selected from (C1-C6)-alkyl, F, Cl, Br, CF3, CN, NO2, OR6, C(-O)R6, C(=O)OR6, C(=O)NR6R7, saturated 6-member heterocyclyl with 2 heteroatoms independently selected from N or O, and S(O)2R6, and where said alkyl is optionally substituted with one -OR8 group; R3 denotes H; (C1-C6)-alkyl; (C2-C6)-alkenyl; Cl; Br; OR6; SR6; phenyl; or a 6-member heteroaryl with 1 heteroatom selected from N, where said alkyl and alkenyl are optionally substituted with one group selected from C(=O)OR8, -OR8, -NR8R9; or a saturated 6-member heterocyclyl with 1 heteroatom selected from N or O.

EFFECT: disclosed compounds are used in treating and preventing diseases mediated by insufficient level of glucokinase activity, such as sugar diabetes.

16 cl, 479 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention refers to new benzimidazole derivatives of general formula (I) or to its pharmacologically acceptable salts wherein R1 represents a C6-aryl group which can be substituted by 1-3 groups optionally specified in a group of substitutes (a), or a heterocyclic group which represents pyridyl, dihydrobenzofuranyl, 1,3-benzodioxolyl, tetrahydropyranyl, tetrahydrofuranyl which can be substituted by 1-3 groups optionally specified in a group of substitutes (a), R2 represents a C1-C6 alkyl group, R3 represents a C6-aryl group which can be substituted by 1-2 groups optionally specified in a group of substitutes (a), Q represents a group represented by formula =CH-, or a nitrogen atom and a group of substitutes (a) represents a group consisting of a halogen atom, a C1-C6 alkyl group, a C1-C6 halogenated alkyl group, a carboxyl group, a C2-C7 alkylcarbonyl group, a C2-C7 alkoxycarbonyl group, a C1-C6 alkoxy group, a C1-C6 halogenated alkoxy group, an amino group, a 4-morpholinyl group and a di-C1-C6 alkyl)amino group. Also, the invention refers to a pharmaceutical composition based on a compound of formula (I), to a PPARγ activator/modulator based on the compound of formula (I), to using the compound of formula (I), to a method of reducing blood glucose, to a method of activating PPARγ, a method of treating and/or preventing said pathological conditions.

EFFECT: there are produced new benzimidazole derivatives showing PPARγ modulatory activity.

41 cl, 2 dwg, 6 tbl, 76 ex

FIELD: chemistry.

SUBSTANCE: described are novel benzotriazole UV-absorbers, having absorption spectrum shifted towards the long-wave side with considerable absorption in the region up to 410-420 nm, having general formulae (a)-(k) (structural formula and values of radicals are given in the description), composition which is stabilised with respect to UV radiation and containing novel UV-absorbers, and use of the novel compounds as UV light stabilisers for organic materials.

EFFECT: obtaining novel benzotriazole UV-absorbers, having absorption spectrum shifted towards the long-wave side.

13 cl, 23 ex, 2 tbl

FIELD: chemistry.

SUBSTANCE: invention relates to novel azaindole derivatives, having JAK-2 and JAK-3 kinase inhibiting activity, or pharmaceutically acceptable salts thereof. In formula (I): R3 denotes H; X1 denotes N or CR4; R2 denotes H, COOH, COOR' or CONHR'; R4 denotes H, F, R, OH, OR', COR', COOH, COOR', CONH2 or CN; or R2 and R4, taken together, form a benzene ring optionally substituted with 1-2 R10; R' denotes C1-3-alkyl or C1-3-alkenyl, each optionally substituted 1-2 R5; each R5 is independently selected from CN, unsubstituted C1-2alkyl, or two groups R5 together with a carbon atom with which they are bonded form a cyclopropyl ring; each R10 is independently selected from halogen, OCH3 or OH; R1 denotes or , R is H or denotes C1-2alkyl, optionally substituted with 1-3 R11; R6 denotes C1-4alkyl, optionally substituted with 1-5 R12; values of radicals R7 -R9, ring A, R11 -R14. The invention also relates to a pharmaceutical composition containing said compounds and a method of treating or reducing severity of a pathological condition such as allergy, asthma, amyotrophic lateral sclerosis, multiocular sclerosis, graft rejection, rheumatoid arthritis, solid malignant tumour, haematologic malignant disease, leukaemia, lymphoma and myeloproliferative disorders.

EFFECT: high efficiency of using the compounds.

41 cl, 6 ex, 6 tbl

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of general formula , where R1 denotes OH, OPO3H2 or OCOR5; R2 denotes H, OH or OPO3H2; A denotes N or CR6; R3 denotes fluorine; R4 denotes H, C1-3alkyl or C3-6cycloalkyl; R5 denotes an alanine residue; R6 denotes H, C1-6alkoxy group or halogen; and n=0 or 1; and to pharmaceutically acceptable salts of compounds of formula I. The invention also relates to a pharmaceutical composition having antibacterial activity, and to use of compounds of formula I to obtain a medicinal agent for preventing or treating bacterial infections.

EFFECT: compounds of formula I, having antibacterial activity.

14 cl, 3 dwg, 2 tbl, 14 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a compound having chemical structure of formula II , all salts and stereoisomers thereof, where the value of radicals D, A2 and B are as described in paragraph 1 of the claim. The invention also relates to a composition having activity as a c-kit and c-fms modulator, a method of treating a subject suffering from a disease or condition mediated by c-kit and c-fms and a kit for modulating c-kit and c-fms.

EFFECT: novel compounds which can be useful in treating c-kit-mediated diseases or conditions and/or c-fms-mediated diseases or conditions are obtained and described.

21 cl, 44 ex

Polycyclic compound // 2451685

FIELD: medicine, pharmaceutics.

SUBSTANCE: described is a new polycyclic compound with general formula (I-1) and (1-3) or a pharmaceutically acceptable salt thereof where X1- -CR1 =CR2 - where R1 and R2 independently stand for hydrogen or C1-6 alkyl while Het stands for a radical of the following formulae: that may be substituted 1-3 times additionally described is a pharmaceutical composition containing such compound and intended for prevention or treatment of diseases caused by β-amyloid.

EFFECT: production of a pharmaceutical composition prevention or treatment of diseases caused by β-amyloid.

7 cl, 392 ex, 12 tbl

FIELD: chemistry.

SUBSTANCE: present invention relates to substituted imidazopyridine derivatives of general formula (I) or enantiomers, diastereomers and tautomers and pharmaceutically acceptable salts thereof, in which A denotes -NH-, -CH2-, -CH2-CH2- or a bond; X denotes phenyl, phenyl condensed with a saturated heterocyclic 5- or 6-member ring, where the heterocyclic ring can contain one or two heteroatoms selected from O and N, and where the heterocyclic ring can further be substituted with an oxo group, a 6-member saturated heterocyclyl containing O as a heteroatom, a 5-6-member heteroaryl containing 1 or 2 heteroatoms selected from N, O and S, and where each phenyl and heteroaryl is possibly substituted with 1 to 2 R14 and/or 1 substitute R4b and/or 1 substitute R5; R1 and R2 are independently selected from the following groups: C1-6-alkyl and C1-6-alkylene-C3-7-cycloalkyl, and where each alkyl is possibly substituted with a OH group, or R1 and R2 together with the nitrogen atom with which they are bonded form a 5-6-member ring which is possibly substituted with one substitute selected from C1-6-alkyl and O-C1-6-alkyl; R4b denotes C(O)NH2, C(O)OH, C(O)NH-C1-6-alkyl, C(O)N-(C1.6-alkyl)2, SO2-C1-6-alkyl, oxo group, and where the ring is at least partially saturated, NH2, NH-C1-6-alkyl, N-(C1-6-alkyl)2; R5 denotes a 6-member heteroaryl containing N as a heteroatom; R3 denotes -(CR8R9)n-T; R8 and R9 are independently selected from the following groups: H and C1-6-alkyl; n equals 1, 2, 3, 4, 5 or 6; T denotes or NR12R13; R10 denotes H, NH2, OH, C1-6-alkyl, possibly substituted with one OH, a halogen atom, NH(C1-6-alkyl) or N(C1-6-alkyl)2; q equals 1 or 2; Y denotes CH2, NR11 or O; R11 denotes H, or C1-6-alkyl; R12 and R13 are independently selected from the following groups: H, C1-6-alkyl, C1-6-alkynyl, (CH2)0-2-C3-7-cycloalkyl, and C1-6-alkylene-O- C1-6-alkyl, where C1-6-alkyl is possibly substituted with one halogen; R14 denotes a halogen atom, CN, C1-6-alkyl, possibly substituted with 1-3 substitutes selected from halogen atom, OH, O- C1-6-alkyl, O-C(O)C1-6-alkyl, O- C1-6-alkyl, possibly substituted with one substitute selected from OH, O- C1-6-alkyl, and O-C(O) C1-6-alkyl, or OH. The invention also relates to a pharmaceutical composition based on the compound of formula (I).

EFFECT: novel imidazopyridine derivatives are obtained, which can be used as melanocortin-4 receptor modulators.

17 cl, 8 tbl, 22 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: this invention relates to compounds that may be applied for HIV infection treatment or prevention or for AIDS or AIDS-associated complex treatment. According to the invention, the compounds represent compounds with formula I, where A stands for A1 , A2 , A3 or A4 and R1, R2, R3, R4a, R4b, R5, R6, Ar, X1, X2, X4, X4 and X5 having values specified in the patent claim. Additionally, this invention relates to a pharmaceutical composition containing the said compounds.

EFFECT: production of compounds possessing inhibition activity with regard to HIV reverse transcriptase.

22 cl, 3 tbl, 29 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to field of cellular molecular biology and represents application of 3-bromo-fascaplysine as medication which inhibits activity of p53 nuclear transcription factor and inducing activity of AP-1 nuclear transcription factor.

EFFECT: invention ensures extension of arsenal of medications which inhibit activity of p53 nuclear transcription factor and induce activity of AP-1 nuclear transcription factor.

2 dwg

FIELD: medicine, pharmaceutics.

SUBSTANCE: claimed is application of complex of tris-(2-hydroxyethyl)amine with zink bis-(2-methylphenoxyacetate) [cresoxyzinkatrane] of formula (HOCH2CH2)3N·Zn(OOCCH2OC6H4CH3-2)2 as stimulator of cytokine activity of total triptophanyl-tRNK synthetase. Demonstrated is increase of total triptophanyl-tRNK synthetase by 50% in comparison with control in dose 5 mg/kg with intramuscular introduction during 2 months; introduction of cresoxyzinkatrane in the same dose but together (simultaneously) with cholesterol during 3 months also produces expressed effect - increase of TRSase level.

EFFECT: invention can be used in medicine and biology as basis for creation of medications of anti-sclerosis action, for instance, for prevention of sclerotic affection of blood vessels.

1 dwg

FIELD: process engineering.

SUBSTANCE: invention relates to production of magnetic iron-bearing nanoparticles to be used in medicine. Proposed method comprises cultivating bacteria Klebsiella oxytoca educed from sapropel of Borovoe Lake, Krasnoyarsk Region, and growing of biomass Then, centrifugation is performed to produce precipitate bearing ferrihydrite and biomass is destructed by ultrasound to isolate ferrihydrite magnetic nanoparticles. Note here that biomass cultivation and growing are executed using iron citrate for 7-10 days to produce precipitate of bacterial cultures. After biomass destruction, precipitates are centrifuged, washed by water and acetone, and treated with NaOH to produce 20%-solution. Then, hatching is performed for an hour to wash precipitates with distilled water with addition of NaCl to neutral pH. Thereafter, precipitates are isolated, washed to produce stable aqueous sol based on ferrihydrite nanoparticles and obtained sol is racked.

EFFECT: stable aqueous sol based on ferrihydrite nanoparticles.

4 dwg, 2 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention refers to new benzimidazole derivatives of general formula (I) or to its pharmacologically acceptable salts wherein R1 represents a C6-aryl group which can be substituted by 1-3 groups optionally specified in a group of substitutes (a), or a heterocyclic group which represents pyridyl, dihydrobenzofuranyl, 1,3-benzodioxolyl, tetrahydropyranyl, tetrahydrofuranyl which can be substituted by 1-3 groups optionally specified in a group of substitutes (a), R2 represents a C1-C6 alkyl group, R3 represents a C6-aryl group which can be substituted by 1-2 groups optionally specified in a group of substitutes (a), Q represents a group represented by formula =CH-, or a nitrogen atom and a group of substitutes (a) represents a group consisting of a halogen atom, a C1-C6 alkyl group, a C1-C6 halogenated alkyl group, a carboxyl group, a C2-C7 alkylcarbonyl group, a C2-C7 alkoxycarbonyl group, a C1-C6 alkoxy group, a C1-C6 halogenated alkoxy group, an amino group, a 4-morpholinyl group and a di-C1-C6 alkyl)amino group. Also, the invention refers to a pharmaceutical composition based on a compound of formula (I), to a PPARγ activator/modulator based on the compound of formula (I), to using the compound of formula (I), to a method of reducing blood glucose, to a method of activating PPARγ, a method of treating and/or preventing said pathological conditions.

EFFECT: there are produced new benzimidazole derivatives showing PPARγ modulatory activity.

41 cl, 2 dwg, 6 tbl, 76 ex

FIELD: medicine.

SUBSTANCE: invention refers to medicine, namely physiotherapy, and may be used for laserophoresis of biologically active substances of higher molecular weight. What is used is a low-intensity laser emission (LILE) by alternating various wave lengths and power densities every second day. At wave length 632-638 nm, power density makes 10-40 mWt/cm2. At wave length 780-785 nm, power density makes 20-90 mWt/cm2. Length of the exposure on one area makes 0.5-1 minute. Length of one session does not exceed 15 minutes.

EFFECT: implementing the method provides higher volumes of the substance of higher molecular weight introduced by laserophoresis in treating various dermatological diseases and eliminating cosmetic defects ensure by more optimal distribution of the introduced substance in biotissues.

3 cl, 3 dwg

FIELD: medicine.

SUBSTANCE: invention refers to medicine, namely to gynaecology, and may be used for treating cystic fibrosis of the breast in females of reproductive age. That is ensured by prescribing the burdock root extract Toxidont-May in a dose of 1 teaspoon in 1 glass of warm water 3 times a day for 3 months.

EFFECT: method provides higher clinical effectiveness ensured by anti-oestrogen actions of the preparation caused by stimulating formation of antiproliferative 2OHE1 in hormone-dependent tissues and improving thereby the relation 2-OHE1/16αOHE1 in favour of the first with no side effects.

2 ex

FIELD: medicine.

SUBSTANCE: invention refers to medicine, namely to gynaecology, and may be used for treating cystic fibrosis of the breast in females of reproductive age. That is ensured by prescribing the Burdock Seed preparation 3 capsules 3 times a day with meal for 6 weeks.

EFFECT: method provides higher clinical effectiveness in cystic fibrosis of the breast ensured by antiproliferative action of the preparation: accurate decrease in tumour necrosis factor alpha (TNF-α) responsible for stimulation of proliferative processes and increase in the content of interleukin-10 (IL10) showing antiproliferative action, and normalisation of a prolactin level with no side effects; and also provides extended range of products used for treating nonneoplastic diseases of the breast.

2 ex, 2 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention refers to immunology and biotechnology. There are offered versions of a TNF-alpha polypeptide wherein a number of heavy-chain single domain antibodies is equal to two. What is described is coding nucleic acid. There are disclosed versions of the compositions, a polypeptide-based kit, as well as versions of using it. What is described is a method for producing the polypeptide with using nucleic acid.

EFFECT: use of the invention provides the substantial growth of cytotoxicity lC50 (of the order of 10-9) that can find further application in therapy of TNFα-mediated disorders.

52 cl, 18 dwg, 11 tbl, 9 ex

FIELD: medicine.

SUBSTANCE: invention refers to medicine and aims at enteral detoxification accompanying treating immune disorders. It involves prescribing a relaxant prebiotic and an enterosorbent. The relaxant prebiotic is introduced in a therapeutic dose 8-12 hours prior to the introduction of the enterosorbent. Once a day in the therapeutic course of 3-5 days. If the relaxant action of the prebiotic appeared to be ineffective, it is prescribed again in the half therapeutic dose. Lactulose is used as said prebiotic. The enterosorbent is activated carbon, Polysorb MP, Enterosgel, Lactofiltrum.

EFFECT: method provides higher clinical effectiveness in the diseases accompanied by immune dysfunctions that is ensured by enteral body detoxification.

1 ex, 3 cl

FIELD: chemistry.

SUBSTANCE: invention relates to a compound of general formula (I), salts and solvates thereof as ligands for G-protein conjugated receptors, , as well as a library consisting of elements which are compounds of formula (I). In general formula (I) , y equals 1 or 2; z equals 0; X denotes -CO-(Y)k-(R1)n, or SO2-(Y)k-(R1)n; k equals 0; each R1 is independently selected from hydrogen or alkyl, haloalkyl, alkoxy, haloalkoxy, alkenyl, alkynyl, alkylamino, alkylaminoalkyl, alkylaminodialkyl, having an alkylaminotrialkyl charge or having an alkylcarboxylate charge from 1-20 carbon atoms; or each R1 is independently selected from fluorine, chlorine, bromine, iodine, hydroxy, oxyalkyl, amino, aminoalkyl, aminodialkyl, having the charge of aminotrialkyl or a carboxylate radical; n is an integer from 1 to m, where m is the maximum number of allowable substitutes; R1 contains a carbon atom next to the carbonyl group of carbonamide or the sulphonyl group of sulphanilamide, which is di-substituted or identical or different groups selected from: alkyl, haloalkyl, alkoxy, haloakoxy, alkenyl, alkynyl and aklylamino radical; and the carbon atom next to the carbonyl group of carbonamide or the sulphonyl group of sulphanilamide in R1 forms essentially tetrahedral valence-bond angles.

EFFECT: obtaining a compound, salt or solvates thereof for use as ligands for G-protein conjugated receptors.

4 cl, 4 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to new hydrated N-fullerene-amino acids of general formula C60(H)3{NH(CH2)nCOOH}3·xH2O, wherein C60 represents fullerene, n = 5-7, x = 8-10, which possess herpes virus, influenza virus, HIV activity, as well as anticancer and antipsoriatic activity. The invention refers to a method for preparing said fullerene amino acids and based pharmaceutical compositions.

EFFECT: preparing new hydrated N-fullerene-amino acids.

5 cl, 28 tbl, 10 ex

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