Novel aminopyridine derivatives having aurora a selective inhibitory action

FIELD: chemistry.

SUBSTANCE: invention relates to a compound of general formula where: R1 denotes COORa1, CONRa2Ra2', CONRa4ORa4', where: each of Ra1 and Ra4 denotes a hydrogen atom; each of Ra2 and Ra2' denotes a hydrogen atom; Ra4' denotes a lower alkyl; or R1 denotes a heterocyclic group selected from the following groups, where Y2 denotes a hydrogen atom or a lower alkyl: R2 denotes O, S, SO, SO2; R3 denotes a phenyl which is substituted with 2 substitutes selected from halogen, CF3; X2 denotes CH or N; W denotes the following residue: where: W1 denotes CH or S; W2 denotes CH; W3 denotes C or N; and at least one of W1, W2 and W3 denotes a carbon atom; or pharmaceutically acceptable salt or ester thereof. The invention also relates to a pharmaceutical composition having Avrora A selective inhibitory action, which, along with a pharmaceutically acceptable carrier or diluent, contains at least one compound of formula I a an active ingredient.

EFFECT: aminopyridine or aminopyrazine derivatives which inhibit growth of tumour cells based on Avrora A kinase selective inhibitory action.

11 cl, 3 tbl, 24 ex

 

The technical field to which the invention relates.

The present invention relates to new aminopyridinium derived that are applicable in the pharmaceutical field, and more specifically, to aminopyridinium derivatives, which inhibit the growth of tumor cells on the basis of selective inhibitory activity against Aurora kinase a and have anti-tumor effect, and selective Aurora kinase inhibitor and antitumor agent containing such derivatives.

The level of technology

The Aurora kinase is a serine/trionychinae involved in cell division. Currently there are three subtypes of the kinase Aurora A, b and C, which are vysokoekonomichny each other. Aurora a is involved in the maturation and distribution of the centrosome or in the formation of the body of the spindle. On the other hand, it is believed that Aurora is involved in aggregation and conjugation of chromosomes, verification (control) point of the spindle and the division of the cytoplasm [Nat. Rev. Mol. Cell Biol., No.4, pp.842-854]. It is also believed that Aurora With acts similarly as a result of interaction with Aurora In [J. Biol. Chem., Epub ahead (2004)]. On the basis of the fact that in most cancer cells was confirmed by high expression of Aurora kinase A; that high expression of Aurora kinase a in normal cells leads to transformation of lines n is malinich cells of rodents and the like, it is believed that Aurora A, which is one of the oncogenes, should be a suitable target for anti-cancer drugs [EMBO J., No. 17, page 3052-3065 (1998)].

According to another report cancer cells, where Aurora is expressed in A high degree, have resistance to paclitaxel [Cancer Cell, Vol. 3, pp. 51-62 (2003)]. At the same time in respect of the Aurora kinase inhibitor is considered that the development of drugs that are selective to certain subtype, is a difficult task, given the high homology among subtypes, structural analysis of the protein and the like; and although there are reports of drugs, such as ZM447439, which simultaneously inhibit both Aurora A and Aurora B [J. Cell Biol., No. 161, pp. 267-280 (2003); J. Cell Biol., No. 161, pp. 281-294, (2003); Nat. Med., No. 10, pages 262-267, (2004)], messages about drugs, selective against Aurora A, unknown. Thus, these messages antitumor effect described only for the case where you enter only one drug, which simultaneously inhibits both Aurora A and Aurora B. in Addition, it was also reported that in medicine, which simultaneously inhibits both Aurora A and Aurora B inhibition activity against kinase Aurora weakens the activity of paclitaxel [J. Cell Biol., No. 161, pp. 281-294, (2003)].

Now were on the Ana patent application, related compounds with inhibitory activity against Aurora kinase (WO 02/057259, U.S. patent No. 6664247 etc), and patent applications relating to aminopyridinium derived, were also submitted (U.S. patent No. 6586424 etc). Under these circumstances, the authors of the present invention filed a patent application relating to aminopyridinium derivative having excellent selective inhibitory activity against Aurora A (WO 2006/046734).

Description of the invention

Problems that should be solved by the present invention consist in the creation of new aminopyridine derivatives, which have an excellent selective inhibitory activity against Aurora A and inhibitory activity against the growth of cells on the basis of the above, as well as in achieving the synergistic action by the combined application with other antitumor agent(s). In addition, the problems that should be solved by the present invention also consist in creating, in the case of oral administration, new aminopyridine derivatives, which have an excellent selective inhibitory activity against Aurora A.

To solve the above problems, the authors of the present invention have synthesized a number of new aminopyridine derivatives and found that the connection is expressed by the following formula (I), based on the above, has excellent selective inhibitory activity against Aurora A and inhibitory activity against the growth of cells and reaches the synergistic action by the combined application with other anticancer means, thereby carrying out the invention. As for those types of cancer that cannot be cured with known anticancer agents such as paclitaxel, because of side effects or resistance to the drug, it is impossible to apply a sufficient amount of such funds, it is expected that oral administration of the compounds according to the invention, or a combination of the introduction of the compounds according to the invention with other anticancer tool will give excellent anti-tumor effects (including increased activity due to other anticancer agent) and the effect on the reduction of the side effects.

Thus, the invention relates to a compound of General formula I:

where:

R1represents a hydrogen atom, F, CN, COORa1, CONRa2Ra2', NRa3CORa3', CONRa4ORa4', NRa5CONRa5'Ra5, NRa6COORa6', SO2NRa7Ra7', NRa8SO2Ra8', CORa9, SO2Ra10, NO2, R a11or NRa12Ra12',

where:

each of Ra1, Ra3, Ra4, Ra5, Ra6and Ra8independently represents a hydrogen atom or lower alkyl;

each of Ra2, Ra2', Ra5', Ra5, Ra7, Ra7', Ra12and Ra12'independently represents a hydrogen atom or lower alkyl which may be substituted by one or more identical or different substituents selected from the <group-Deputy L1>where <group-Deputy L1> represents a halogen atom, hydroxy, nitro, cyano, amino, carbarnoyl, aminosulfonyl, imino, lower alkylamino, di(lower)alkylamino, lower alkylsulfonyl, lower alkylsulfonyl, lower alkoxy, lower alkoxycarbonyl, lower alkoxycarbonyl, lower alkanoyl, lower alkanoyloxy, lower alkylthio and carboxyl; however, provided that each of Ra2and Ra2'; Ra5'and Ra5; Ra7and Ra7'; Ra12and Ra12'independently, together with the nitrogen atom to which they are attached, may form a 5-membered or 6-membered aromatic or aliphatic heterocyclic group which may be substituted by one or more identical or different substituents selected from the <group-Deputy L2>where <group-replace the ü L 2> represents a halogen atom, hydroxy, amino and hydroxymethyl;

each of Ra3', Ra4', Ra6', Ra8', Ra9, Ra10and Ra11independently represents a hydrogen atom or lower alkyl which may be substituted by one or more identical or different substituents selected from the <group-Deputy L1>or

R1represents lower alkyl which may be substituted by one or more identical or different substituents selected from the <group-Deputy M>, where <group-Deputy M> represents a halogen atom, hydroxy, nitro, cyano, amino, carbarnoyl, aminosulfonyl, imino, lower alkylamino, di(lower)alkylamino, lower alkylsulfonyl, lower alkylsulfonyl, lower alkoxy, lower alkoxycarbonyl, lower alkoxycarbonyl, lower alkanoyl, lower alkanoyloxy, lower alkylthio and carboxyl; or

R1represents a heterocyclic group selected from the following groups, where Y1and Y2are the same or different and each represents a hydrogen atom or lower alkyl which may be substituted:

R2represents O, S, SO, SO2, NH, NRbor CRc1Rc2where Rbisone lower alkyl, which may be substituted, and Rc1and Rc2that may be the same or different, represent a hydrogen atom or lower alkyl;

R3represents phenyl which may be substituted;

X2represents CH, CX2aor N, where:

X2arepresents lower alkyl; or

X2ais a Deputy chosen from <group-Deputy A1>or lower alkyl which is substituted by one or more identical or different substituents selected from the <group-Deputy A1>where <group-Deputy A1> represents a halogen atom; cyano; hydroxy; lower alkylamino; di(lower)alkylamino; lower alkoxy which may be substituted by one or more hydroxy groups; lower alkylthio; and lower alkylsulfonyl; or

X2arepresents COORx1, CONRx2Rx3, NHCORx1, NHCONRx2Rx3, NHSO2NRx2Rx3, NRx4Rx5or CH2NRx4Rx5where:

Rx1represents a hydrogen atom or lower alkyl which may be substituted;

each of Rx2and Rx3that may be the same or different, represents a hydrogen atom, lower alkyl which may be substituted, or cycloalkyl, which may be substituted; or, alter ative, Rx2and Rx3together with the nitrogen atom to which they are attached, form a 5 - or 6-membered aliphatic heterocyclic group which contains at least one atom selected from N, O and S, and which may be substituted; and

Rx4and Rx5that may be the same or different, represent a hydrogen atom, lower alkyl which may be substituted, or cycloalkyl, which may be substituted; or

X2arepresents 5 - or 6-membered aliphatic heterocyclic group which contains at least one atom selected from N, O and S, and which may be substituted, in which two hydrogen atoms that are attached to the same carbon atom aliphatic heterocyclic group may be substituted by exography, and the adjacent two carbon atoms constituting the aliphatic heterocyclic ring may form a double bond; or lower alkyl, substituted aliphatic heterocyclic group; or

X2arepresents 5 - or 6-membered aromatic heterocyclic group which contains at least one atom selected from N, O and S, and which may be substituted; or lower alkyl which is substituted by an aromatic heterocyclic group;

W represents the following balance:

where:

W1represents CH, N, NH, O or S;

W2represents CH, CW2aN NW2b, O or S, where each W2aand W2bindependently represents a hydrogen atom, halogen atom, cyano, lower alkyl containing from one to two carbon atoms, cycloalkyl containing three to five carbon atoms, or lower alkyl containing from one to two carbon atoms, which may be substituted by one or more halogen atoms;

W3represents C or N; and,

at least one of W1, W2and W3represents a carbon atom; however, two of W1, W2and W3at the same time cannot represent O and S,

or its pharmaceutically acceptable salt or complex ether.

The invention also relates to a combined preparation for simultaneous, separate or sequential injection in the treatment of cancer, containing two separate drug, which are:

* preparation containing, together with a pharmaceutically acceptable carrier or diluent, the compound represented by the above formula (I)or its pharmaceutically acceptable salt or ester; and

* preparation containing, together with a pharmaceutically acceptable carrier or diluent one antitumor agent selected from the group consisting whom she of antitumor alkylating funds antitumor antimetabolites, antitumor antibiotics, anticancer agents of plant origin, anticancer coordination compounds of platinum antitumor derivative camptothecin, antitumor tyrosine kinase inhibitors, monoclonal antibodies, interferons, biological response modifiers, and other anticancer agents, as well as their pharmaceutically acceptable salt(s) or of ester(s), where

antitumor alkylating agent is a N-oxide nitrogen mustard, cyclophosphamide, ifosfamide, melphalan, busulfan, mitobronitol, carboquone, thiotepa, ranimustine, nimustine, temozolomide or carmustine;

antineoplastic antimetabolite is a methotrexate, 6-mercaptopurine, mercaptopurine, 5-fluorouracil, tegafur, doxifluridine, carmofur, cytarabine, ocfosfate citarabina enocitabine, S-1, gemcitabine, fludarabine or the disodium pemetrexed;

antitumor antibiotic is an actinomycin D, doxorubicin, daunorubicin, neocarzinostatin, bleomycin, peplomycin, mitomycin C, aclarubicin, pirarubicin, epirubicin, zinostatin stimulater, idarubitsin, sirolimus or valrubicin;

antitumor agent of plant origin is a vincristine, vinblastine, vindesine, etop is Ded, sobuzoxane, docetaxel, paclitaxel or vinorelbine;

antitumor coordinating the platinum compound is cisplatin, carboplatin, nedaplatin or oxaliplatin;

antitumor derived camptothecin represents irinotecan, topotecan or camptothecin;

antitumor tyrosine kinase inhibitor is gefitinib, imatinib, sorafenib, sunitinib, dasatinib or erlotinib;

monoclonal antibody is a cetuximab, rituximab, bevacizumab, alemtuzumab or trastuzumab;

interferon is an interferon α, interferon α-2a, interferon α-2b, interferon β, interferon γ-1a or interferon γ-n1;

biological response modifier is a christening, lentinan, sizofiran, picibanil or ubenimex; and

another anti-cancer agent is a mitoxantrone, L-asparaginase, procarbazine, dacarbazine, hydroxycarbamide, pentostatin, tretinoin, alefacept, darbepoietin-alpha, anastrozole, exemestane, bikalutamid, leuprorelin, flutamide, fulvestrant, Octanate pegaptanib, denileukin diftitox, aldesleukin, thyrotropin alpha, arsenic trioxide, bortezomib, capecitabine or goserelin.

The invention additionally relates to pharmaceutical compositions containing, together with a pharmaceutically acceptable wear elem or diluent connection, represented by the above 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, anticancer coordination compounds of platinum antitumor derivative camptothecin, antitumor tyrosine kinase inhibitors, monoclonal antibodies, biological response modifiers, and other anticancer agents (here the definition of each antitumor agents is the same as in the above definition) or their pharmaceutically acceptable salt, or a complex ester.

In addition, the invention additionally relates to a method for treatment of cancer, comprising 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, antitumor cf is the funds of vegetable origin, anticancer coordination compounds of platinum antitumor derivative camptothecin, antitumor tyrosine kinase inhibitors, monoclonal antibodies, interferons, biological response modifiers, and other anticancer agents (here the definition of each antitumor agents is the same as in the above definition) or their pharmaceutically acceptable salt, or a complex ester.

In addition, the invention relates to the use of a selective inhibitor of Aurora A, for the manufacture of a medicinal product intended for the treatment of cancer; and to the use of a selective inhibitor of Aurora A, in combination with an antitumor agent for the manufacture of a medicinal product intended for the treatment of cancer; and also relates to a method of treating cancer in a mammal (particularly in humans), which includes the introduction referred to the mammal a therapeutically effective amount of a selective inhibitor of Aurora A; and to a method of treating cancer in a mammal (particularly a human)which includes the introduction referred to the mammal a therapeutically effective amount of a selective inhibitor of Aurora A in combination with a therapeutically effective amount of anti-cancer drugs.

The invention relates to pharmaceutical to the notizie, containing as an active ingredient, a selective inhibitor of Aurora A; and to pharmaceutical compositions containing as active ingredient a selective inhibitor of Aurora A, together with antitumor agent.

Next will be explained the symbols and terms used in the present description of the invention.

The term "lower alkyl" in the above formula (I) represents an alkyl group with a linear or branched chain containing from 1 to 6 carbon atoms, and examples of such groups include, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl and hexyl, among which preferred is methyl.

The term "cycloalkyl" in the above formula (I) denotes a 3-8-membered aliphatic cyclic group, such as, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl.

The term "heterocyclic group" in the formula (I) refers to the "aromatic heterocyclic group" or "aliphatic heterocyclic group". In this description, the term "aromatic heterocyclic group" refers to aromatic heterocyclic group containing, in addition to the atom(s) of carbon, at least one heteroatom such as nitrogen atom, oxygen atom or the like, and examples of such groups include 5-7-membered monocyclic heterocyclics group, heterocyclic group condensed with a loop formed by condensation 3-8-membered cycle with monocyclic heterocyclic group, etc. In particular, we can mention thienyl group, pyrrolidino group, thiazolidine group, imidazolidinyl group, pyrazolidine group, oxazolidinyl group, pyridyloxy group, personilnya group, pyrimidinyl group, pyridazinyl group, isoxazolyl group, izohinolinove group, isoindolyl group, indazolinone group, indolenine group, khinoksalinona group, pinolillo group, benzoimidazolyl group, benzofuranyl group, etc. on the other hand, the term "aliphatic heterocyclic group" refers to saturated or unsaturated aliphatic heterocyclic group containing in addition to the atom(s) of carbon, at least one atom selected from a nitrogen atom, oxygen atom and sulfur atom, and containing monocyclic cycle or bicyclic or tricyclic condensed cycle. Examples of such groups include azetidinol group, pyrrolidinyl group, piperidinyl group, piperazinilnom group, morpholinopropan, tetrahydropyranyloxy group, imidazolidinyl group, thiomorpholine, tetrahydropyridine group, tetrahydroisoquinoline group, etc.

The term "5 - or 6-is certain aliphatic heterocyclic group" in the above formula (I) denotes a 5 - or 6-membered aliphatic cyclic group, containing at least one atom selected from a nitrogen atom, oxygen atom and sulfur atom in addition to carbon atoms, and examples of such groups include pyrrolidinyl, piperidinyl, piperazinil, morpholino, tetrahydrofuranyl, imidazolidinyl, thiomorpholine. In addition, in the aliphatic heterocyclic group two hydrogen atoms that are attached to the same carbon atom may be replaced by exography, as well as the adjacent carbon atoms constituting the cycle of the aliphatic heterocyclic group may be connected by a double bond.

The term "5 - or 6-membered aromatic heterocyclic group" in the above formula (I) denotes a 5 - or 6-membered aromatic cyclic group containing at least one atom selected from a nitrogen atom, oxygen atom and sulfur atom in addition to carbon atoms, and examples of such groups include thienyl, pyrrolyl, furyl, thiazolyl, imidazolyl and oxazolyl.

The term "halogen atom" in the above formula (I) represents, for example, fluorine atom, chlorine atom, bromine atom or iodine atom. Among them, preferred is, for example, fluorine atom, chlorine atom or bromine atom.

The term "lower alkylamino" in the above formula (I) refers to a group in which the amino group is N-substituted by the above-described "lower alkyl", and an example of what such groups include N-methylamino, N-ethylamino, N-propylamino, N-isopropylamino, N-butylamino, N-isobutylamino, N-tert-butylamino, N-pentylamine and N-hexylamino.

The term "di(lower)alkylamino" in the above formula (I) refers to a group in which the amino group is N,N-disubstituted above-described "lower alkyl", and examples of such groups include N,N-dimethylamino, N,N-diethylamino, N,N-dipropylamino, N,N-diisopropylamino, N,N-dibutylamino, N,N-diisobutylamine, N,N-di-tert-butylamino, N,N-diphenhydamine, N,N-digoxigenin, N-ethyl-N-methylamino and N-methyl-N-propylamino.

The term "lower alkylsulfonyl" in the above formula (I) refers to a group in which the above-described "lower alkyl" is attached to sulfonyl, and examples of such groups include methylsulphonyl, ethylsulfonyl and butylsulfonyl.

The term "lower alkylsulfonamides" in the above formula (I) refers to a group in which the above-described "lower alkylsulfonyl" is attached to the amino group, and examples of such groups include methylsulfonylamino, ethylsulfonyl, butylsulfonyl.

The term "lower alkoxy" in the above formula (I) refers to a group in which "lower alkyl" is attached to the oxygen atom, and examples of such groups include methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, tert-butoxy, pentyloxy, neopentylene, hexyloxy isohexane.

The term "lower alkoxycarbonyl" in the above formula (I) refers to a group in which "lower alkoxy" is attached to the carbonyl, and examples of such groups include methoxycarbonyl, etoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, isobutoxide, second-butoxycarbonyl, tert-butoxycarbonyl, pentyloxybenzoyl, neopentylglycol, hexyloxybenzoyl and isohexadecane.

The term "lower alkoxycarbonyl" in the above formula (I) refers to a group in which the lower alkoxycarbonyl" attached to the amino group, and examples of such groups include methoxycarbonylamino, ethoxycarbonylethyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonylamino, solutionline, sec-butoxycarbonylamino, tert-butoxycarbonylamino, ventilatsioonile, neopentecostalism, hexyloxyphenyl, isohexadecane.

The term "lower alkanoyl" in the above formula (I) refers to a group in which the above-described "lower alkyl" is attached to the carbonyl, and examples of such groups include acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl, pivaloyl and pentanoyl.

The term "lower alkanoyloxy" in the above formula (I) refers to a group in which the above-described "lower alkanoyl" attached to the atom is oxygen, and examples of such groups include the atomic charges, propionyloxy, butyryloxy, isobutyryloxy, valeriote, isovalerianic, pivaloyloxy, pentanoate.

The term "lower alkylthio" in the above formula (I) denotes Deputy, where the above-described "lower alkyl" is attached to the sulfur atom, and examples of such groups include methylthio, ethylthio, butylthio.

The term "selective inhibitor of Aurora A, used in the present description of the invention, is a compound or drug that selectively inhibits Aurora A in comparison with Aurora B. "Selective inhibitor of Aurora A is preferably a compound or a drug inhibiting activity which is against Aurora A, at least ten times greater activity against Aurora B; and more preferably, the compound or drug, inhibiting activity which is against Aurora A, at least a hundred times higher activity against Aurora B.

Explanation of the term "its pharmaceutically acceptable salt of ester" or the term "pharmaceutically acceptable carrier or diluent used in the description of the invention, will be given later.

The term "cancer treatment"used in the description of the invention, means inhibiting the growth of cancer cells by introducing against the tumor means the patient with cancer. Preferably such treatment makes it possible to retrogression growth of cancer tumors, that is, a measurable reduction of the size of the tumor. More preferably, this treatment completely removes a cancerous tumor.

The term "cancer"used in the description of the invention refers to a solid cancer and malignant disease of hematopoietic system. In the present description, examples of solid cancers include brain tumor, head and neck cancer, esophageal cancer, thyroid cancer, small cell lung cancer, non-small cell lung cancer, breast cancer, stomach cancer, cancer of the gallbladder and bile duct, liver cancer, pancreatic cancer, cancer of the colon, colorectal cancer, ovarian cancer, horionepiteliome, uterine cancer, cervical cancer, cancer of the renal pelvis and ureter, bladder cancer, prostate cancer, penile cancer, testicular cancer, embryonal cancer, Wilms tumor, skin cancer, malignant melanoma, neuroblastoma, osteosarcoma, Ewing's sarcoma and soft tissue sarcoma. On the other hand, examples of malignant disease of hematopoietic system include acute leukemia, chronic lymphocytic leukemia, chronic miliitary leukemia, true polycythemia, malignant lymphoma, multiple myeloma and nahodkinskuju lymphoma.

The term "prep the rat", used in the description of the invention, includes preparations for oral administration and preparations for parenteral administration. Examples of drugs for oral administration include tablets, capsules, powders and granules, while examples of parenteral preparations include sterilized liquid preparations such as solutions or suspensions, in particular, injection or infusion through a drip. Preferably they represent intravenous injection or intravenous infusion through a drip, and more preferably intravenous infusion through a drip.

The term "a combined preparation"used in the description of the invention relates to preparations containing two or more drugs for simultaneous, separate or sequential injection in the treatment, and this drug can be a drug or pharmaceutical composition of the so-called dial-type. The term "a combined preparation" also includes the preparation containing one or more drugs, optionally combined with a combination drug containing two separate drug used in the treatment of cancer.

The above-described two separate drug can additionally be combined in combination with a pharmaceutically acceptable carrier or diluent, at least with od is their drug, containing at least one antitumor agent selected from the group consisting of antitumor alkylating funds, antitumor antimetabolites, antitumor antibiotics, anticancer agents of plant origin, anticancer coordination compounds of platinum antitumor derivative camptothecin, antitumor tyrosine kinase inhibitors, monoclonal antibodies, interferons, biological response modifiers, and other anticancer agents (here the definition of each antitumor agents is the same as in the above definition), or their pharmaceutically acceptable salt, or a complex ester. In this case, the above-mentioned at least one drug, which combined advanced, can be administered simultaneously, separately or sequentially with respect to two separate drugs. For example, a combination drug that contains three drugs, may include one that consists of preparation, including the preparation containing the compound represented by the above formula (I), a preparation containing 5-fluorouracil, and the drug containing leucovorin.

Here, in the above-mentioned combined drug either or both of the individual drug can be a drug for p is moralnego introduction; and one can be a preparation for oral administration, while the other may be a preparation for parenteral administration (injection or infusion through a drip).

The preparation according to the invention can typically contain a therapeutically effective amount of the compounds according to the invention together with a pharmaceutically acceptable carrier or diluent. It is believed that such methods of preparation of medicines is well known and should represent the technical information that is well-known to specialists in this field. Preferably the preparations for oral administration, intravenous infusion through a drip or injection can be obtained in combination with a pharmaceutically acceptable carrier or diluent in a variety of ways that are well known in this field.

In the case of the combined preparation according to the invention, the term "introduction"used in the present description of the invention relates to parenteral introduction and/or oral introduction and preferably for oral administration. Thus, with the introduction of combined drug both the introduction can be parenteral, one administration can be parenteral, while another may be oral; or both the introduction can be the feather the material. Preferably both drugs in combined oral medications are injected. Here, the term "parenteral administration"represents, for example, an intravenous, subcutaneous administration or intramuscular administration, and preferably it is an intravenous. Even when combined and entered three or more drugs, each drug can be administered orally.

In one of the embodiments of the present invention compound represented by the above formula (I)can be administered simultaneously with other antitumor agent(s). In addition, you can enter the connection represented by the above formula (I), and then another antitumor agent; or, alternatively, you can enter another antitumor agent, and then the connection represented by the above formula (I). Also you can enter the connection represented by the above formula (I), and then after some time separately to enter another antitumor agent; or, alternatively, you can enter another antitumor agent, and then after some time, to separately enter the compound represented by the above formula (I). The order and time interval introduction accordingly may be the chosen specialist in this field in accordance for example, with the preparation containing the compound represented by the above formula (I), and a preparation containing an antitumor agent, which is used in combination with it, the type of cancer cells being treated, and the condition of the patient. For example, in the case of the introduction of compounds represented by the above formula (I), and paclitaxel or docetaxel preferably first administered paclitaxel or docetaxel, and then after some time, sequentially or separately to enter the compound represented by the above formula (I).

The term "simultaneously"as used in the description of the invention refers to the use of drugs for the treatment substantially at the same time, while the term "separately" refers to the individual use of drugs for the treatment at different times, so that, for example, one tool used in the first day, and another tool used on the second day of treatment. The term "sequentially" refers to the use of drugs in such manner that, for example, first use one tool, and after a preset period of time, use a different tool for treatment.

The term "antineoplastic alkylating agent used in the present description of the invention, refers to the alkylating agent with antitumor activity, and C is followed by a session in the term "alkylating agent" generally refers to the tool, giving the alkyl group in the alkylation reaction in which a hydrogen atom of an organic compound substituted alkyl group. The term "antineoplastic alkylating agent" can be illustrated by examples in the form of N-oxide nitrogen mustard, cyclophosphamide, ifosfamide, melphalan, busulfan, mitobronitol, carboquone, thiotepa, ranimustine, nimustine, temosolomida or carmustine.

The term "antineoplastic antimetabolite used in the description of the invention, refers to the antimetabolite with antineoplastic activity, and here the term "antimetabolite" includes, in a broad sense, substances that disrupt the normal metabolism, and substances that inhibit the transfer system of electrons to prevent the formation of energy-rich intermediate products, due to their structural or functional similarities to metabolites that are important for living organisms (such as vitamins, coenzymes, amino acids and sugars). The term "antineoplastic antimetabolites can be illustrated by the examples in the form of methotrexate, 6-mercaptopurine, mercaptopurine, 5-fluorouracil, tegafur, doxifluridine, carmofur, tsitarabina, ocfosfate citarabina enocitabine, S-1, gemcitabine, fludarabine or disodium of pemetrexed, and preferred are 5-fluorouracil, S-1, gemc the Tabin, etc.

The term "antitumor antibiotic used in the description of the invention relates to antibiotic with antitumor activity, and here "antibiotic" includes substances which are produced by microorganisms or obtained by organic synthesis and inhibit cell growth and other functions of microorganisms and other living organisms. The term "antitumor antibiotic" can be illustrated by examples as actinomycin D, doxorubicin, daunorubicin, neocarzinostatin, bleomycin, peplomycin, mitomycin C, aclarubicin, pirarubicin, epirubicin, zinostatin of stimulater, idarubitsina, sirolimus or valrubicin.

The term "antitumor agent of plant origin used in the description of the invention, includes compounds having antitumor activities, which are derived from plants or compounds obtained by applying the above mentioned compounds chemical modification. The term "antitumor agent of plant origin" can be illustrated by examples in the form of vincristine, vinblastine, vindesine, etoposide, sobuzoxane, docetaxel, paclitaxel and vinorelbine, and are preferred docetaxel and paclitaxel.

The term "antitumor derived camptothecin"used in the description of the research Institute of the invention, refers to compounds that are structurally related to camptothecin and inhibit the growth of cancer cells, including camptothecin itself. The term "antitumor derived camptothecin" is not specifically limited, although it can be illustrated by the examples in the form of camptothecin, 10-hydroxycamptothecin, topotecan, irinotecan or 9-aminocamptothecin, that are preferred camptothecin, topotecan and irinotecan. In addition, irinotecan converted in the process of metabolism in vivo and has anti-tumor effects as SN-38. It is believed that the mechanism of action and activity of derivatives of camptothecin almost should be the same as camptothecin (see, for example, Nitta and others, Gan to Depending Ryoho, 14, 850-857 (1987)).

The term "anticancer coordination compound of platinum (platinum complex)"used in the description of the invention, refers to the coordination of the platinum compound with antitumor activity, and the term "coordination compound of platinum" refers here to the coordination compound of platinum, which provides platinum in ionic form. Preferred platinum compounds include cisplatin; CIS-diamminedichloroplatinum(II)-ion; chloride chlorine(Diethylenetriamine)platinum (II); dichloro(Ethylenediamine)platinum (II)diamine-(1,1-cyclobuta dicarboxylato)platinum (II) (carboplatin); spiroplatin; iproplatin; diamine-(2-ethylmalonate)platinum (II); etilendiaminmonoatsetat (II); Aqua(1,2-diaminocyclohexane)selfadaptation (II); Aqua(1,2-diaminocyclohexane)melanoplinae (II); (1,2-diaminocyclohexane)melanoplinae (II); (4-carboxylato)(1,2-diaminocyclohexane)platinum (II); (1,2-diaminocyclohexane)-(isocitrate)platinum(II); (1,2-diaminocyclohexane)occultopedia (II); ormaplatin; tetraploid; carboplatin, nedaplatin and oxaliplatin, and are preferred carboplatin or oxaliplatin. In addition, well-known and are commercially available and/or can be obtained by the person skilled in the art using traditional techniques other anticancer coordination compounds of platinum, mentioned in the description.

The term "antitumor tyrosine kinase inhibitor used in the description of the invention refers to a tyrosine kinase inhibitor with antitumor activity, and the term "tyrosine kinase inhibitor" refers here to the chemical substance, the inhibitory "tyrosinekinase", which transfers the γ-phosphate group of ATP to the hydroxy-group of a specific tyrosine in the protein. The term "antitumor tyrosine kinase inhibitor" can be illustrated by examples in the form of gefitinib, imatinib, sorafenib, sunitinib, dasatinib or erlotinib.

The term "monoclonal anti the lo", used in the description of the invention, which is also known as odolonline antibody refers to an antibody produced by the cell producing a monoclonal antibody, and their examples include cetuximab, bevacizumab, rituximab, alemtuzumab and trastuzumab.

The term "interferon"as used in the description of the invention refers to interferon having anti-tumor activity, and represents a glycoprotein with molecular weight of approximately 20,000, which is produced and secreted by most animal cells during viral infection. He has not only the effect of inhibiting the growth of the virus, but also various immunoaffinity mechanisms, including inhibition of cell growth (in particular, tumor cells) and increased activity of natural killer cells, therefore is one of the types of cytokines. Examples of "interferon" include interferon α, interferon α-2a, interferon α-2b, interferon β, interferon γ-1a, and interferon γ-n1.

The term "biological response modifier"used in the description of the invention, refers to the so-called biological response modifier or BRM and is usually a generic term for substances or medicinal products intended for modification of the protective mechanisms of living organisms or biological responses, such as ugiwanie, the growth or differentiation of cells of tissues, in order to direct them for the benefit of the individual against the tumor, infection or other diseases. Examples of "biological response modifier" include baptisms, lentinan, sizofiran, picibanil and ubenimex.

The term "other antitumor agent"used in the description of the invention relates to antitumor agent, which does not belong to any of the above funds with antitumor activities. Examples of the "other antitumor agents include mitoxantrone, L-asparaginase, procarbazine, dacarbazine, hydroxycarbamide, pentostatin, tretinoin, alefacept, darbepoietin Alfa, anastrozole, exemestane, bikalutamid, leiprorelina, flutamide, fulvestrant, Octanate pegaptanib, denileukin diftitox, aldesleukin, thyrotropin alpha, arsenic trioxide, bortezomib, capecitabine, and goserelin.

All of the above terms "anticancer alkylating agent", "antineoplastic antimetabolite", "antitumor antibiotic", "antitumor agent of plant origin", "anticancer coordination compound of platinum", "antitumor derived camptothecin", "antitumor tyrosine kinase inhibitor", "monoclonal antibody, interferon, biological response modifier and the other is an antitumor agent" known and are either commercially available, or can be obtained by the person skilled in the art using methods known in essence, or well known, or by using traditional methods. The method of producing gefitinib described, for example, in U.S. patent No. 5770599; receive cetuximab described, for example, in the application WO 96/40210; the method of obtaining bevacizumab described, for example, in the application WO 94/10202; the method of obtaining oxaliplatin described, for example, in U.S. patent No. 5420319 and 5959133; the method of receiving gemcitabine described, for example, in U.S. patent No. 5434254 and 5223608; and a method of producing camptothecin described in U.S. patents№№ 5162532, 5247089, 5191082, 5200524, 5243050 and 5321140; the method of receiving irinotecan described, for example, in the patent U.S. No. 4604463; a method of producing topotecan described, for example, in U.S. patent No. 5734056; the method of obtaining temosolomida described, for example, in the patent JP-B No. 4-5029; and a method of producing rituximab described, for example, in the patent JP-W No. 2-503143.

The above-mentioned antitumor alkylating tools are commercially available, as illustrated by the following examples: N-oxide nitrogen mustard from Mitsubishi Pharma Corp. as drug Nitrogen (brand Nitromin); cyclophosphamide from Shionogi & Co., Ltd. in the medication Endoxan (brand Endoxan); ifosfamide from the company Shionogi & Co., Ltd. in the medication Itemid (brand Ifomide); melphalan from GlaxoSmithKline Corp. as ven the rata Alkeran (brand name Alkeran); the busulfan from the company Takeda Pharmaceutical Co., Ltd. as drug Marlin (brand Mablin); mitobronitol from Kyorin Pharmaceutical Co., Ltd. in the medication Mabry (brand Myebrol); carboquone from Sankyo Co., Ltd. as drug Esquinas (brand Esquinon); thiotepa from Sumitomo Pharmaceutical Co., Ltd. as drug Despain (brand Tespamin); ranimustine from Mitsubishi Pharma Corp. as drug Camerin (brand Cymerin); nimustine from Sankyo Co., Ltd. as drug Nigran (brand Nidran); temozolomide from Schering Corp. as drug Temodar (brand name Temodar); and carmustin from Guilford Pharmaceuticals Inc. in the medication Gliadel Wafer (brand Gliadel Wafer).

The above-mentioned antitumor antimetabolites are commercially available that are illustrated in the following examples: methotrexate from Takeda Pharmaceutical Co., Ltd. in the medication Methotrexate (brand name Levitra); 6-mercaptopurine riboside from Aventis Corp. in the medication Thioinosine (brand Thioinosine); mercaptopurine from the company Takeda Pharmaceutical Co., Ltd. as drug Leukeran (brand Leukerin); 5-fluorouracil from Kyowa Hakko Kogyo Co., Ltd. in the form of the drug 5-FU (trade mark); tegafur from Taiho Pharmaceutical Co., Ltd. as drug Futraful (brand Futraful); doxifluridine from Nippon Roche Co., Ltd. in the medication Furtulon (the trademark Furutulon); carmofur from Yamanouchi Pharmaceutical Co., Ltd. in the medication Amatur (brand Yamafur); cytarabine from Nippon Shinyaku Co., Ltd. in the medication Zerocid (brand Cylocide); ocfosfate tsitarabina from Nippon Kayaku Co., Ltd. in the medication Stressed (brand Strasid); enocitabine from the company Asahi Kasei Corp. in the medication Sunrain (brand Sanrabin); S-1 from Taiho Pharmaceutical Co., Ltd. in the form of the drug TS-1 (trade mark); gemcitabine company Eli Lilly & Co. in the form of the drug Gemzar (brand name Gemzar); fludarabine from Nippon Schering Co., Ltd. in the form of the drug Fludara (brand Fludara); and the disodium pemetrexed from Eli Lilly & Co. in preparation for Kolya (brand name Alimta).

The above-mentioned antitumor antibiotics are commercially available, as illustrated by the following examples: actinomycin D from Banyu Pharmaceutical Co., Ltd. in the medication Cosmegen (brand name Cosmegen); doxorubicin from the company Kyowa Hakko Kogyo Co., Ltd. in the medication Adriatic (brand Adriacin); daunorubicin from the company Meiji Seika Kaisha Ltd. as drug Daunomycin (Daunomycin); neocarzinostatin from Yamanouchi Pharmaceutical Co., Ltd. in the medication Neocarzinostatin (brand Neocarzinostatin); bleomycin from Nippon Kayaku Co., Ltd. as drug Bleo (brand Bleo); paromycin from Nippon Kayaku Co., Ltd. in the medication Pepro (brand Pepro); mitomi is in C from Kyowa Hakko Kogyo Co., Ltd. in the form of the drug Mitomycin (brand Mitomycin); aclarubicin from Yamanouchi Pharmaceutical Co., Ltd. as drug Alazine (brand Aclacinon); pirarubicin from Nippon Kayaku Co., Ltd. in the medication Pirarubicin (brand Pinorubicin); epirubicin from Pharmacia Corp. as drug Farmorubicin (brand Pharmorubicin); zinostatin stimulater from Yamanouchi Pharmaceutical Co., Ltd. as drug Smancs (brand Smancs); idarubitsin from Pharmacia Corp. in the medication Idamycin (brand Idamycin); sirolimus from Wyeth Corp. as drug Rapamune (brand name Rapamune); and valrubicin from Anthra Pharmaceuticals Inc. in the medication Valstar (brand Valstar).

The above-mentioned antitumor agents of vegetable origin are commercially available, as illustrated by the following examples: vincristine from the company Shionogi & Co., Ltd. in the medication Oncovin (brand name Oncovin); vinblastine from Kyorin Pharmaceutical Co., Ltd. in the form of the drug Vinblastine (brand Vinblastine); vindesine from the company Shionogi & Co., Ltd. in the medication Filesin (brand Fildesin); etoposide from Nippon Kayaku Co., Ltd. as drug Lastet (brand Lastet); sobuzoxane from Zenyaku Kogyo Co., Ltd. in the medication Pyrazolin (brand Perazolin); docetaxel from Aventis Corp. in the medication Taxoter (brand Taxstere); paclitaxel from the company Bristol-Myers Squibb Co. in the form of the drug Taxol (brand name Taxol); and vinorelbine from Kyowa Hakko Kogyo Co., Ltd. in the medication Navelbine (brand Navelbine).

The above-mentioned antitumor coordination compounds of platinum are available for sale, as illustrated by the following examples: cisplatin from Nippon Kayaku Co., Ltd. in view of the preparation of the Rand (trade mark Randa); carboplatin from Bristol-Myers Squibb Co. as drug Paraplatin (brand name Paraplatin); nedaplatin from the company Shionogi & Co., Ltd. in the medication of Aquaplan (brand Aqupla); and oxaliplatin from Sanofi-Synthelabo Co. as drug Eloxatin (trademark Eloxatin).

The above-mentioned antitumor derivatives of camptothecin are commercially available, as illustrated by the following examples: irinotecan from the company Yakult Honsha Co., Ltd. as Campto (brand Campto); topotecan from GlaxoSmithKline Corp. in the medication Cosmegen (brand Hycamtin); and camptothecin from the company Aldrich Chemical Co., Inc., U.S.A.

The above-mentioned antitumor tyrosine kinase inhibitors are commercially available, as illustrated by the following examples: gefitinib from AstraZeneca Corp. as drug Iressa (brand name Iressa), imatinib from Novartis AG in the form of Glivec (brand Gleevec); sorafenib from the company Bayer in the form of ven is the ATA Nexavar (brand name Nexavar); sunitinib from Pfizer in the form of the drug Sutent (brand name Sutent); dasatinib from Bristol Myers Squibb in the form of the drug Sprycel (brand name Sprycel); and erlotinib from the company OSI Pharmaceuticals Inc. in the medication Tarceva (brand name Tarceva).

The above-mentioned monoclonal antibodies are commercially available, as illustrated by the following examples: cetuximab company Bristol-Myers Squibb Co. in the medication Erbitux (brand name Erbitux), bevacizumab company Genentech, Inc. in the form of the drug Avastin (brand name Avastin); rituximab from the company Biogen Idee Inc. in the form of the drug Rituxan (brand name Rituxan); alemtuzumab from Berlex Inc. as drug Campath (brand name Campath); and trastuzumab from Chugai Pharmaceutical Co., Ltd. in the form of the drug Herceptin (brand name Herceptin).

The above-mentioned interferons are commercially available, as illustrated by the following examples: interferon-α from Sumitomo Pharmaceutical Co., Ltd. in the medication Sumiferon (brand Sumiferon); interferon α-2a from the company Takeda Pharmaceutical Co., Ltd. in the medication Chaperon (brand Canferon-A); interferon α-2b from Schering-Plough Corp. in the medication intron a (brand name Intron A)interferon β from Mochida Pharmaceutical Co., Ltd. in the medication IFNβ (trade mark); interferon γ-1a from the company Shionogi & Co., Ltd. in the medication Immunomax-γ (brand Imunomax-γ); and int is Heron γ-n1 from the company Otsuka Pharmaceutical Co., Ltd. as drug Gamma (brand Ogamma).

The above-mentioned biological response modifiers are commercially available, as illustrated by the following examples: baptisms from the company Sankyo Co., Ltd. in the medication Christening (brand Krestin); lentinan from Aventis Corp. in the medication Lentinan (brand Lentinan); sizofiran from Kaken Seiyaku Co., Ltd. in the medication Coniferin (brand Sonifiran); picibanil from Chugai Pharmaceutical Co., Ltd. as drug Picibanil (brand Picibanil); and ubenimex from Nippon Kayaku Co., Ltd. in the medication Bestatin (brand Bestatin).

The above-mentioned other antineoplastic agents are commercially available, as illustrated by the following examples: mitoxantrone from Wyeth Lederle Japan, Ltd. in the medication Novantrone (brand Novantrone); L-asparaginase from Kyowa Hakko Kogyo Co., Ltd. in the medication Leonas (brand Leunase); procarbazine from Nippon Roche Co., Ltd. as drug Natulan (brand Natulan); dacarbazine from Kyowa Hakko Kogyo Co., Ltd. in the form of the drug Dacarbazine (brand Dacarbazine); hydroxycarbamide from Bristol-Myers Squibb Co. in the medication Hydrea (brand Hydrea); pentostatin from a company Called Oyobi Kessei Ryoho Kenkyusho as drug Kaporin (brand Coforin); tretinoin from Nippon Roche Co., Ltd. in the medication Vesanoid (brand Veanoid); alefacept from the company Biogen Idee Inc. in the medication AMEVIVE (brand name Amevive); darbepoietin-alpha from Amgen Inc. in the medication Aranesp (brand name Aranesp); anastrozole from AstraZeneca Corp. in the form of the drug arimidex (brand name Arimidex), exemestane from Pfizer Inc. in the medication Aromasin (brand name Aromasin); bikalutamid from AstraZeneca Corp. in the medication Casodex (brand Casodex); leiprorelina from the company Takeda Pharmaceutical Co., Ltd. in the medication Leuplin (brand name : Leuplin); flutamide from Schering-Plough Corp. in the medication Eulexin (brand name Eulexin); fulvestrant from AstraZeneca Corp. in the form of the drug Faslodex (brand Faslodex); octandre pegaptanib from Gilead Sciences, Inc. as drug Macugen (brand Macugen); denileukin diftitox from Ligand Pharmaceuticals Inc. in the medication a touch of a button (brand Ontak); aldesleukin from Chiron Corp. in the medication Proleukin (brand name Proleukin); thyrotropin-alpha company Genzyme Corp. as drug Thyrogen (brand Thyrogen); arsenic trioxide from the company Cell Therapeutics, Inc. as drug Trisenox (brand Trisenox); bortezomib from the company Millennium Pharmaceuticals, Inc. in the medication Velcade (brand name Velcade); capecitabine from Hoffmann-La Roche, Ltd. in the form of the drug xeloda (brand name Xeloda); and goserelin from AstraZeneca Corp. as p is of eparate the Zoladex (brand name Zoladex).

The term "anticancer agent"used in the description of the invention includes the above-described "antitumor alkylating agent", "antineoplastic antimetabolite", "antitumor antibiotic", "antitumor agent of plant origin", "anticancer coordination compound of platinum", "antitumor derived camptothecin", "antitumor tyrosine kinase inhibitor", "monoclonal antibody, interferon, biological response modifier " and "other antitumor agent".

The term "aminopyridine derivative"used in the description of the invention, includes, but is not limited to, any compound containing pyridyloxy group or a group similar to the pyridine group, any of which is substituted by an amino group. This is displayed by connecting the above-described General formula (I) and preferably any of the compounds mentioned below from (a) to (e): a compound which is:

(a) TRANS-4-(3-chloro-2-pertenece)-1-((6-(1,3-thiazol-2-ylamino)pyridine-2-yl)methyl)cyclohexanecarbonyl acid (example 1 and 2);

(b) TRANS-4-(2-fluoro-3-(trifluoromethyl)phenoxy)-1-((6-(1,3-thiazol-2-ylamino)pyridine-2-yl)methyl)cyclohexanecarbonyl acid (example 4);

(c) TRANS-4-(2,3-dichlorophenoxy)-1-((6-(1,3-thiazol-2-ylamino)pyridine-2-yl)methyl)cyclohexanone the new acid (example 5);

(d) TRANS-4-(2-fluoro-3-(trifluoromethyl)phenoxy)-1-((6-(1H-pyrazole-3-ylamino)pyridine-2-yl)methyl)cyclohexanecarbonyl acid (example 7);

(e) TRANS-4-(3-chloro-2-pertenece)-1-((6-(1H-pyrazole-3-ylamino)pyrazin-2-yl)methyl)cyclohexanecarboxylic (example 11);

(f) 5-(TRANS-4-(2-fluoro-3-(trifluoromethyl)phenoxy)-1-((6-(1H-pyrazole-3-ylamino)pyridine-2-yl)methyl)cyclohexyl)-1,3,4-oxadiazol-2(3H)-he (example 13);

(g) 5-(TRANS-4-(3-chloro-2-pertenece)-1-((6-(1H-pyrazole-3-ylamino)pyridine-2-yl)methyl)cyclohexyl)-1,3,4-oxadiazol-2(3H)-he (example 14);

(h) 5-(TRANS-4-(3-chloro-2-pertenece)-1-((6-(1H-pyrazole-3-ylamino)pyrazin-2-yl)methyl)cyclohexyl)-1,3,4-oxadiazol-2(3H)-he (example 17); or

(i) 5-(TRANS-4-((2,3-dichlorophenyl)sulfonyl)-1-((6-(1H-pyrazole-3-ylamino)pyridine-2-yl)methyl)cyclohexyl)-1,3,4-oxadiazol-2(3H)-he (example 24),

or its pharmaceutically acceptable salt or ester.

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

R1represents a hydrogen atom, F, CN, COORa1, CONRa2Ra2', NRa3CORa3', CONRa4ORa4', NRa5CONRa5'Ra5, NRa6COORa6', SO2NRa7Ra7', NRa8SO2Ra8', CORa9, SO2Ra10, NO2ORa11or NRa12Ra12',

where:

each of Ra1, Ra3, Ra4, Ra5, R and Ra8independently represents a hydrogen atom or lower alkyl;

each of Ra2, Ra2', Ra5', Ra5, Ra7, Ra7', Ra12and Ra12'independently represents a hydrogen atom or lower alkyl which may be substituted by one or more, same or different substituents selected from the <group-Deputy L1>where <group-Deputy L1> represents a halogen atom, hydroxy, nitro, cyano, amino, carbarnoyl, aminosulfonyl, imino, lower alkylamino, di(lower)alkylamino, lower alkylsulfonyl, lower alkylsulfonyl, lower alkoxy, lower alkoxycarbonyl, lower alkoxycarbonyl, lower alkanoyl, lower alkanoyloxy, lower alkylthio and carboxyl; however, provided that each of Ra2and Ra2'; Ra5'and Ra5; Ra7and Ra7'; Ra12and Ra12'independently, together with the nitrogen atom to which they are attached, may form a 5-membered or 6-membered aromatic or aliphatic heterocyclic group which may be substituted by one or more, same or different substituents selected from the <group-Deputy L2>where <group-Deputy L2> represents a halogen atom, hydroxy, amino, and hydroxymethyl;

ka is each of R a3', Ra4', Ra6', Ra8', Ra9, Ra10and Ra11independently represents a hydrogen atom or lower alkyl which may be substituted by one or more, same or different substituents selected from the <group-Deputy L1>or

R1represents lower alkyl which may be substituted by one or more, same or different substituents selected from the <group-Deputy M>where <group-Deputy M> represents a halogen atom, hydroxy, nitro, cyano, amino, carbarnoyl, aminosulfonyl, imino, lower alkylamino, di(lower)alkylamino, lower alkylsulfonyl, lower alkylsulfonyl, lower alkoxy, lower alkoxycarbonyl, lower alkoxycarbonyl, lower alkanoyl, lower alkanoyloxy, lower alkylthio and carboxyl; or

R1represents a heterocyclic group selected from the following groups, where Y1and Y2are the same or different, and each represents a hydrogen atom or lower alkyl which may be substituted:

Preferably R1represents OH, COOH or CONRa2Ra2'in which Ra2and Ra2'are the same or different, and each represents the Wallpaper hydrogen atom or lower alkyl, containing from one to three carbon atoms; or R1selected from the following groups:

<group-Deputy L1> represents a halogen atom, hydroxy, nitro, cyano, amino, carbarnoyl, aminosulfonyl, imino, lower alkylamino, di(lower)alkylamino, lower alkylsulfonyl, lower alkylsulfonyl, lower alkoxy, lower alkoxycarbonyl, lower alkoxycarbonyl, lower alkanoyl, lower alkanoyloxy, lower alkylthio and carboxyl; preferably represents a hydrogen atom, hydroxy, amino, carbarnoyl, lower alkylamino, lower alkylamino and lower alkoxy.

<group-Deputy L2> represents a halogen atom, hydroxy, amino and hydroxymethyl; preferably hydroxy and hydroxymethyl.

<group-Deputy M> represents a halogen atom, hydroxy, nitro, cyano, amino, carbarnoyl, aminosulfonyl, imino, lower alkylamino, di(lower)alkylamino, lower alkylsulfonyl, lower alkylsulfonyl, lower alkoxy, lower alkoxycarbonyl, lower alkoxycarbonyl, lower alkanoyl, lower alkanoyloxy, lower alkylthio and carboxyl; preferably hydroxy, carbarnoyl, aminosulfonyl, lower alkylsulfonamides and carboxyl.

R2the stand is made by an O, S, SO, SO2, NH, NRbor CRc1Rc2in which Rbrepresents lower alkyl which may be substituted, and Rc1and Rc2that may be the same or different, represent a hydrogen atom or lower alkyl which may be substituted.

Preferably R2represents O, S, SO or SO2; more preferably O.

R3represents phenyl which may be substituted; preferably R3represents phenyl, which is substituted; more preferably R3represents phenyl, which is in the 2nd and 3rd positions is substituted by two identical or different substituents selected from F, Cl, CF3and CN.

X2represents CH, CX2aor N, where:

X2arepresents lower alkyl; or

X2ais a Deputy chosen from <group-Deputy A1>or lower alkyl which is substituted by one or more, same or different substituents selected from the <group-Deputy A1>where <group-Deputy A1> represents a halogen atom; cyano; hydroxy; lower alkylamino; di(lower)alkylamino; lower alkoxy which may be substituted by one or more hydroxy groups; lower alkylthio; and lower alkylsulfonyl; or

X2adepict is to place a COOR x1, CONRx2Rx3, NHCORx1, NHCONRx2Rx3, NHSO2NRx2Rx3, NRx4Rx5or CH2NRx4Rx5where:

Rx1represents a hydrogen atom or lower alkyl which may be substituted;

each of Rx2and Rx3that may be the same or different, represents a hydrogen atom, lower alkyl which may be substituted, or cycloalkyl, which may be substituted; or alternatively, Rx2and Rx3together with the nitrogen atom to which they are attached, form a 5 - or 6-membered aliphatic heterocyclic group which contains at least one atom selected from N, O and S, and which may be substituted; and

Rx4and Rx5that may be the same or different, represent a hydrogen atom, lower alkyl which may be substituted, or cycloalkyl, which may be substituted; or

X2arepresents 5 - or 6-membered aliphatic heterocyclic group which contains at least one atom selected from N, O and S, and which may be substituted, in which two hydrogen atoms that are attached to the same carbon atom aliphatic heterocyclic group may be substituted by exography, and the adjacent two carbon atoms constituting the aliphatic heterocyclic ring, m is able to form a double bond; or lower alkyl, substituted aliphatic heterocyclic group; or

X2arepresents 5 - or 6-membered aromatic heterocyclic group which contains at least one atom selected from N, O and S, and which may be substituted; or lower alkyl which is substituted by an aromatic heterocyclic group.

Preferably X2represents CH, CX2aor N, where X2arepresents lower alkyl.

More preferably X2represents CH or N.

<group-Deputy A1> represents a halogen atom; cyano; hydroxy; lower alkylamino; di(lower)alkylamino; lower alkoxy which may be substituted by one or more hydroxy groups; lower alkylthio; and lower alkylsulfonyl; preferably halogen atom, hydroxy, lower alkylamino and lower alkylsulfonyl.

W represents the following balance:

where:

W1represents CH, N, NH, O or S;

W2represents CH, CW2aN NW2b, O or S, where each of W2aand W2bindependently represents a hydrogen atom, halogen atom, cyano, lower alkyl containing from one to two carbon atoms, cycloalkyl containing three to five carbon atoms, or lower alkyl, the content is of AMI from one to two carbon atoms, which may be substituted by one or more halogen atoms;

W3represents C or N; and

at least one of W1, W2and W3represents a carbon atom; however, two of W1, W2and W3at the same time cannot represent O and S.

W is preferably selected from:

W is more preferably chosen from:

where W2arepresents a hydrogen atom, halogen atom, cyano or methyl which may be substituted by one to three fluorine atoms.

In particular, W is preferably selected from:

Even more preferably, W is selected from:

The preferred implementation of the compounds represented by the above General formula (I)can also be expressed as follows:

(1) the Compound of the above formula (I) or its pharmaceutically acceptable salt or ester, where W is selected from:

(2) the Compound described in paragraph (1), or its pharmaceutically acceptable salt or ester, where R3represents phenyl, which is in the 2nd and 3rd positions is substituted by two identical or different substituents selected from F, Cl, CF3and CN.

(3) is Connected to the e, described in paragraph (2), or its pharmaceutically acceptable salt or ester, where <group-Deputy L1> represents a halogen atom, hydroxy, amino, carbarnoyl, lower alkylamino, di(lower)alkylamino and lower alkoxy; and <group-Deputy M> represents hydroxy, carbarnoyl, aminosulfonyl, lower alkylsulfonamides and carboxyl.

(4) the Compound described in paragraph (3), or its pharmaceutically acceptable salt or ester where X2represents CH or N.

(5) the Compound described in paragraph (4), or its pharmaceutically acceptable salt or ester, where R1represents OH, COOH or CONRa2Ra2'where Ra2and Ra2'are the same or different and each represents a hydrogen atom or a lower alkyl containing from one to three carbon atoms; or R1selected from the following groups:

and R2represents O, S, SO or SO2.

(6) the Compound described in paragraph (5), or its pharmaceutically acceptable salt or ester, where:

W is selected from:

where W2arepresents a hydrogen atom, halogen atom, cyano or methyl which may be substituted by one to three fluorine atoms.

(7) the Compound described in paragraph (6), or its pharmaceutically reception who will be salt or ester, where W represents any of the following residues:

(8) the Compound, which is:

(a) TRANS-4-(3-chloro-2-pertenece)-1-((6-(1,3-thiazol-2-ylamino)pyridine-2-yl)methyl)cyclohexanecarbonyl acid;

(b) TRANS-4-(2-fluoro-3-(trifluoromethyl)phenoxy)-1-((6-(1,3-thiazol-2-ylamino)pyridine-2-yl)methyl)cyclohexanecarbonyl acid;

(c) TRANS-4-(2,3-dichlorophenoxy)-1-((6-(1,3-thiazol-2-ylamino)pyridine-2-yl)methyl)cyclohexanecarbonyl acid;

(d) TRANS-4-(2-fluoro-3-(trifluoromethyl)phenoxy)-1-((6-(1H-pyrazole-3-ylamino)pyridine-2-yl)methyl)cyclohexanecarbonyl acid;

(e) TRANS-4-(3-chloro-2-pertenece)-1-((6-(1H-pyrazole-3-ylamino)pyrazin-2-yl)methyl)cyclohexanecarboxylic;

(f) 5-(TRANS-4-(2-fluoro-3-(trifluoromethyl)phenoxy)-1-((6-(1H-pyrazole-3-ylamino)pyridine-2-yl)methyl)cyclohexyl)-1,3,4-oxadiazol-2(3H)-he;

(g) 5-(TRANS-4-(3-chloro-2-pertenece)-1-((6-(1H-pyrazole-3-ylamino)pyridine-2-yl)methyl)cyclohexyl)-1,3,4-oxadiazol-2(3H)-he;

(h) 5-(TRANS-4-(3-chloro-2-pertenece)-1-((6-(1H-pyrazole-3-ylamino)pyrazin-2-yl)methyl)cyclohexyl)-1,3,4-oxadiazol-2(3H)-he; or

(i) 5-(TRANS-4-((2,3-dichlorophenyl)sulfonyl)-1-((6-(1H-pyrazole-3-ylamino)pyridine-2-yl)methyl)cyclohexyl)-1,3,4-oxadiazol-2(3H)-he,

or their pharmaceutically acceptable salt or ester.

Also in yet another embodiment, the invention relates to a compound of General formula (I0 ):

where:

R10represents a hydrogen atom, F, CN, OH, CH2OH, COOH or CONRa10Ra20where Ra10and Ra20that may be the same or different, represent a hydrogen atom or lower alkyl;

R20represents O, S, NH, NRbor CRc1Rc2where Rbrepresents lower alkyl, and Rc1and Rc2that may be the same or different, represent a hydrogen atom or lower alkyl;

R3represents phenyl which may be substituted;

X1represents CH, CX1aor N, where X1arepresents lower alkyl which may be substituted;

X2represents CH, CX2aor N, where:

X2arepresents lower alkyl; or

X2ais a Deputy chosen from <group-Deputy A1>or lower alkyl which is substituted by one or more, same or different substituents selected from the <group-Deputy A1>where <group-Deputy A1> represents a halogen atom; cyano; hydroxy; lower alkylamino; di(lower)alkylamino; lower alkoxy which may be substituted by one or more hydroxy groups; lower alkylthio; and lower alkylsulfonyl; or

X2apredstavljaet a COOR x1, CONRx2Rx3, NHCORx1, NHCONRx2Rx3, NHSO2NRx2Rx3, NRx4Rx5or CH2NRx4Rx5where:

Rx1represents a hydrogen atom or lower alkyl which may be substituted;

each of Rx2and Rx3that may be the same or different, represents a hydrogen atom, lower alkyl which may be substituted, or cycloalkyl, which may be substituted; or alternatively, Rx2and Rx3together with the nitrogen atom to which they are attached, form a 5 - or 6-membered aliphatic heterocyclic group which contains at least one atom selected from N, O and S, and which may be substituted; and

Rx4and Rx5that may be the same or different, represent a hydrogen atom, lower alkyl which may be substituted, or cycloalkyl, which may be substituted; or

X2arepresents 5 - or 6-membered aliphatic heterocyclic group which contains at least one atom selected from N, O and S, and which may be substituted, in which two hydrogen atoms that are attached to the same carbon atom aliphatic heterocyclic group may be substituted by exography, and the adjacent two carbon atoms constituting the aliphatic heterocyclic ring, m is able to form a double bond; or lower alkyl, substituted aliphatic heterocyclic group; or

X2arepresents 5 - or 6-membered aromatic heterocyclic group which contains at least one atom selected from N, O and S, and which may be substituted; or lower alkyl which is substituted by an aromatic heterocyclic group;

provided however, that among X1and X2the number of nitrogen atoms is 0 or 1;

W represents the following balance:

where:

W1represents CH, N, NH, O or S;

W2represents CH, CW2aN NW2b, O or S, where each of W2aand W2bindependently represents a hydrogen atom, halogen atom, cyano, lower alkyl containing from one to two carbon atoms, cycloalkyl containing three to five carbon atoms, or lower alkyl containing from one to two carbon atoms, which may be substituted by one or more halogen atoms;

W3represents C or N; and

at least one of W1, W2and W3represents a carbon atom; however, two of W1, W2and W3at the same time cannot represent O and S,

or its pharmaceutically acceptable salt or complex ether.

In addition, in the combined drug from the retenu, containing two separate drug, preferably any of the two separate drugs, or both, are drugs for oral administration.

Combined preparation according to the invention, containing two separate drug preferably is of this drug, where one of the drugs is a drug containing, together with a pharmaceutically acceptable carrier or diluent, the following connections:

(a) TRANS-4-(3-chloro-2-pertenece)-1-((6-(1,3-thiazol-2-ylamino)pyridine-2-yl)methyl)cyclohexanecarbonyl acid;

(b) TRANS-4-(2-fluoro-3-(trifluoromethyl)phenoxy)-1-((6-(1,3-thiazol-2-ylamino)pyridine-2-yl)methyl)cyclohexanecarbonyl acid;

(c) TRANS-4-(2,3-dichlorophenoxy)-1-((6-(1,3-thiazol-2-ylamino)pyridine-2-yl)methyl)cyclohexanecarbonyl acid;

(d) TRANS-4-(2-fluoro-3-(trifluoromethyl)phenoxy)-1-((6-(1H-pyrazole-3-ylamino)pyridine-2-yl)methyl)cyclohexanecarbonyl acid;

(e) TRANS-4-(3-chloro-2-pertenece)-1-((6-(1H-pyrazole-3-ylamino)pyrazin-2-yl)methyl)cyclohexanecarboxylic;

(f) 5-(TRANS-4-(2-fluoro-3-(trifluoromethyl)phenoxy)-1-((6-(1H-pyrazole-3-ylamino)pyridine-2-yl)methyl)cyclohexyl)-1,3,4-oxadiazol-2(3H)-he;

(g) 5-(TRANS-4-(3-chloro-2-pertenece)-1-((6-(1H-pyrazole-3-ylamino)pyridine-2-yl)methyl)cyclohexyl)-1,3,4-oxadiazol-2(3H)-he;

(h) 5-(TRANS-4-(3-chloro-2-pertenece)-1-((6-(1H-pyrazole-3-ylamino)pyrazin-2-yl)methyl)cyclohexyl)-1,3,4-oxadiazol-2(3H)he; or

(i) 5-(TRANS-4-((2,3-dichlorophenyl)sulfonyl)-1-((6-(1H-pyrazole-3-ylamino)pyridine-2-yl)methyl)cyclohexyl)-1,3,4-oxadiazol-2(3H)-he,

or their pharmaceutically acceptable salt or ester; and

another drug is a drug containing paclitaxel or docetaxel or pharmaceutically acceptable salt or ester together with a pharmaceutically acceptable carrier or diluent.

In addition, the combined preparation containing, together with a pharmaceutically acceptable carrier or diluent two separate drug, according to the invention can optionally be combined, at least one preparation containing an antitumor agent selected from the group consisting of antitumor alkylating funds, antitumor antimetabolites, antitumor antibiotics, anticancer agents of plant origin, anticancer coordination compounds of platinum antitumor derivative camptothecin, antitumor tyrosine kinase inhibitors, monoclonal antibodies, interferons, biological response modifiers, and other anticancer agents (here the definition of each antitumor agents is the same as in the above definition) or pharmaceutically acceptable salt or a complex ester.

<> The pharmaceutical composition according to the invention together with a pharmaceutically acceptable carrier or diluent are also preferably contains the following connections:

(a) TRANS-4-(3-chloro-2-pertenece)-1-((6-(1,3-thiazol-2-ylamino)pyridine-2-yl)methyl)cyclohexanecarbonyl acid;

(b) TRANS-4-(2-fluoro-3-(trifluoromethyl)phenoxy)-1-((6-(1,3-thiazol-2-ylamino)pyridine-2-yl)methyl)cyclohexanecarbonyl acid;

(c) TRANS-4-(2,3-dichlorophenoxy)-1-((6-(1,3-thiazol-2-ylamino)pyridine-2-yl)methyl)cyclohexanecarbonyl acid;

(d) TRANS-4-(2-fluoro-3-(trifluoromethyl)phenoxy)-1-((6-(1H-pyrazole-3-ylamino)pyridine-2-yl)methyl)cyclohexanecarbonyl acid;

(e) TRANS-4-(3-chloro-2-pertenece)-1-((6-(1H-pyrazole-3-ylamino)pyrazin-2-yl)methyl)cyclohexanecarboxylic;

(f) 5-(TRANS-4-(2-fluoro-3-(trifluoromethyl)phenoxy)-1-((6-(1H-pyrazole-3-ylamino)pyridine-2-yl)methyl)cyclohexyl)-1,3,4-oxadiazol-2(3H)-he;

(g) 5-(TRANS-4-(3-chloro-2-pertenece)-1-((6-(1H-pyrazole-3-ylamino)pyridine-2-yl)methyl)cyclohexyl)-1,3,4-oxadiazol-2(3H)-he;

(h) 5-(TRANS-4-(3-chloro-2-pertenece)-1-((6-(1H-pyrazole-3-ylamino)pyrazin-2-yl)methyl)cyclohexyl)-1,3,4-oxadiazol-2(3H)-he; or

(i) 5-(TRANS-4-((2,3-dichlorophenyl)sulfonyl)-1-((6-(1H-pyrazole-3-ylamino)pyridine-2-yl)methyl)cyclohexyl)-1,3,4-oxadiazol-2(3H)-he,

or their pharmaceutically acceptable salt or ester; and paclitaxel or docetaxel or pharmaceutically acceptable salt ilistory ether together with a pharmaceutically acceptable carrier or diluent.

Next will be explained inhibiting activity of the compounds of General formula (I) according to the invention against Aurora A and Aurora B.

Inhibitory activity against Aurora A

(1)Cleaning Aurora A

cDNA His-labeled N-the end of human Aurora kinase A has integrated in expressing vector, which is then highly expressively in Escherichia coli cells BL21-CodonPlus(DE3)-RIL. Cells of Escherichia coli were collected and subjected to lysis, and then His-labeled human protein Aurora A was applied on a Nickel-chelate column and suirable with a column with imidazole. Active fractions were absoluely on a column for gel filtration (demineralization), while receiving the purified enzyme.

(2)Measurement of the activity of Aurora A

The substrate used for measuring the activity of Aurora A was a synthetic peptide (5-FAM (5-carboxyfluorescein)-γ-aminobutyric acid-Ala-Leu-Arg-Arg-Ala-Ser-Leu-Gly-NH2)(SEQ ID NO:1), which was obtained from the company Toray Research Center, Inc.

For the reaction of phosphorylation refer to the way Upstate, Inc. [Kinase ProfilerTMthe test protocols], and were detected phosphorylation of the substrate, using the IMAP method (Molecular Devices Co. Ltd.)(Gaudet EW. and others, J.Biomol.Screen, 8, 164-175(2003)). More specifically, the phosphorylation reaction and detection was carried out as follows.

The phosphorylation reaction was performed using the m 384-tablet the reaction volume was 10 μl/cell. The reaction buffer consisted of 50 mm Tris-chloride buffer (pH of 7.4), 15 mm magnesium acetate, 0.2 mm Ethylenediamine-N,N,N',N'-tetraoxane acid (EDTA). To it was added the purified protein Aurora A, 100 nm peptide substrate and 20 μm adenosine-5'-triphosphate (ATP), and then reaction was carried out at 30°C for 120 minutes.

Then, to complete and to detect the reaction, each well was added to 30 μl of binding reagent (IMAP Progressive Binding Reagent, R7284) IMAP (registered trademark), which was diluted (1:400) 1×MAP binding buffer A (IMAP Progressive Binding Buffer A, 5×stock solution, R7282). The solution was kept in the dark for 60 minutes and then measured the fluorescence polarization using high-performance reader for microplates (wavelength of excitation: 485 nm; emission wavelength: 520 nm).

Into the reaction was added to the system connection is being checked, while preparing a series of dilutions of the compounds in dimethyl sulfoxide (DMSO) and then added to 0.5 μl of this solution for testing in each well. For each solution provided a control well by adding in a hole of 0.5 µl DMSO instead of DMSO solution containing subjected to testing the connection.

Inhibitory activity against Aurora B

(1) Measure the activity of Aurora B (Method A)

For the reaction of phosphorylation applied a set of reagents for analysis IMAP (registered trademark) (Aurora B), provided by Carna Biosciences, Inc., and were detected phosphorylation of the substrate using the IMAP technology. Which set of reagents for analysis consisted of buffer for analysis of complex, consisting of GST-labeled human Aurora B (AurB)/complex His-tagged human proteins INCENP (amino acid sequence: 803-916, AAU04398.1) and a solution of ATP/substrate. Using the same tools, the phosphorylation reaction according to a partially modified the instructions that came with the set, and then detected the phosphorylation of the substrate using the IMAP technology.

For the reaction of phosphorylation used a 384-well plate, and the reaction volume was 10 µl/well. The composition of the reaction buffer (buffer for analysis) consisted of 20 mm HEPES buffer (pH of 7.4), 0.01% of Tween-20 and 2 mm dithiothreitol (DTT). The buffer was added to the complex AurB/complex protein INCENP, 100 nm substrate, 40 μm ATP and 1 mm magnesium salts and then reaction was performed at 25°C for 45 minutes. After that, to complete and detection of reaction in each well was added to 30 μl of binding reagent (IMAP Progressive Binding Reagent, R7284) IMAP (registered trademark), which was diluted (1:400) 1×IMAP binding buffer A (IMAP Progressive Biding Buffer A, 5×stock solution, R7282). The solution was kept in the dark for 60 minutes and then measured the fluorescence polarization using high-performance reader for microplates (wavelength of excitation: 485 nm; emission wavelength: 520 nm).

Into the reaction was added to the system test connection, while preparing a series of dilutions of the compounds in DMSO and then 0.5 μl of this solution was added for testing in each well. For each solution created a control hole, adding a 0.5 µl DMSO instead of DMSO solution containing subjected to testing the connection.

(2)Measurement of the activity of Aurora B (Method B)

(a) Purification of Aurora B

cDNA of human Aurora B, containing His-tag that is connected with the N-end, integrated in expressing vector, then with a high degree expressively in cells of the bacterium Escherichia coli BL21-CodonPlus(DE3)-RIL. Cells of Escherichia coli were collected, subjected to solubilization and then the His-tagged protein Aurora B was adsorbing on a Nickel-chelate column and suirable with a column with imidazole. Active fractions were absoluely on a column for gel filtration (demineralization), while receiving the purified enzyme.

(b) Measuring the activity of Aurora B

When measuring the activity of Aurora B substrate used was a Kemptide (Leu-Arg-Arg-Ala-Ser-Leu-Gly) (SEQ ID NO:2), sintet the ical peptide was provided by Sigma-Aldrich, Inc.

The reaction was carried out using a partially modified method of measuring the activity of Aurora A. the Amount of the reaction liquid was 21.1 μl, and in the composition of the reaction buffer (buffer R2) consisted of 50 mm Tris-cleaners containing hydrochloride buffer (pH of 7.4), 15 mm magnesium acetate, 0.2 mm Ethylenediamine-N,N,N',N'-leads to compounds, which (EDTA). To it was added the purified Aurora B, 100 μm substrate peptide, 100 μm does not contain labels triphosphate (ATP) and 1 µci of ATP labeled with γ33P (2500 CI/mmol or more), and gave the mixture a chance to interact at 30°C for 20 minutes. Then to the reaction system were added 10 μl of 350 mm phosphate buffer to stop the reaction. Substrate peptide was adsorbing on 96-well tablet of paper P81 filter and then repeatedly washed 130 mm phosphate buffer. The radioactivity of the peptide was measured using a liquid scintillation counter. ATP labeled with γ33P was provided by Amersham Biosciences Co., Ltd.

The connection being tested was added to the reaction system, whereby it was preparing a series of dilutions of the compounds in DMSO and 1.1 μl of this solution was added to the reaction system. Control sample provided by adding to the reaction system of 1.1 µl DMSO.

Using the above-mentioned method (when measuring the activity of Aurora B primenalsa A) the results of measurements of activities of Aurora A and Aurora B, shown in table 1. The connection according to the invention had excellent selective inhibitory activity against Aurora A. Similar results were obtained when measuring the activity of Aurora B used method B.

Table 1
ExampleInhibitory activity against Aurora A (IC50nm)Inhibitory activity against Aurora In (IC50nm)ExampleInhibitory activity against Aurora A (IC50nm)Inhibitory activity against Aurora In (IC50nm)
Example 10,0725Example 140,39490
Example 30,1259Example 150,12130
Example 40,1132Example 161,4 800
Example 50,0737Example 170,19670
Example 60,54150Example 180,0839
Example 70,16190Example 190,1953
Example 80,15200Example 200,1570
Example 91,8750Example 210,13210
Example 112,0870Example 220,47690
Example 120,49200Example 23 0,31120
Example 131,0660Example 240,43370

Next will be explained the activity of the compounds of General formula (I) according to the invention for suppressing cell growth.

Method of assessment the pharmaceutical effect using cells

a Reagent

Fetal calf serum (FCS) was provided by Moregate Biotech, nutritional DMEM was provided by Invitrogen Corp. Reagent WST-8 was provided by Kishida Chemical Co., Ltd.

(b) Cells

Cancer cells human cervical (HeLa S3) were obtained from the American Type Culture Collection (ATCC).

c) Method of valuation effect

Prepared cell suspension in DMEM containing 10% FCS, and distributed the cell suspension in 96-well plastic plate with a load of 750 cells/100 microliters per well. Tablet incubated at 37°C overnight in an atmosphere consisting of 95% air and 5% CO2. Prepared calibration solutions of drugs by breeding in dimethyl sulfoxide and was further diluted with DMEM containing 10% FCS. Then the solutions of each of the dilutions were applied to separate the tablet in the hole which was made 100 microlitres cellular WM is ansii per well. The tablet additionally incubated at 37°C for three days in an atmosphere containing 5% CO2and 95% air. Cell growth after incubation was measured by the method of WST-8 (H. Tominaga and other, Anal. Commun., 36, 47-50 (1999)). In this way WST-8 refers to the way in which each well was added 20 microliters solution reagent WST-8, incubation was performed at 37°C for 60 minutes, the tablet is shaken and a colorimetric method to measure the quantity produced of formazane to determine the percentage of inhibition for medicines. Determined the concentration of compound required for 50% growth inhibition (IC50microns).

As can be seen from table 2, the compound according to the invention had excellent inhibitory effect against the growth of cancer cells derived from human (HeLa S3).

Table 2
Inhibitory effect against growth of cells (HeLa S3) (IC50microns)
Example 11,97
Example 33,95
Example 40,83
Example 51,93
Example 61,26
Example 7of 2.21
Example 92,80
Example 111,76
Example 120,90
Example 130,90
Example 140,76
Example 151,15
Example 163,30
Example 170,67
Example 180,34
Example 19of 5.89
Example 200,59
Example 212,22
Example 220,87
Example 230,22
Example 241,13

The method of evaluating the effect of application in the cells of combined drug

a Reagent

Fetal calf serum (FCS) is the had been provided by Moregate Biotech, culture medium DMEM was provided by Invitrogen Corp., docetaxel (brand: Taxere) from Sigma-Aldrich, Inc., and reagent WST-8 from Kishida Chemical Co., Ltd.

(b) Cells

Cells of human malignant tumors of the cervix (HeLa S3) were obtained from the American Type Culture Collection (ATCC).

c) Method of valuation effect

Prepared cell suspension in DMEM containing 10% FCS, and distributed the cell suspension on two 96-well plastic tablets with the load 750 cells/100 microliters per well. The plates were incubated at 37°C overnight in an atmosphere consisting of 95% air and 5% CO2. Preparing the calibration solutions in dimethyl sulfoxide and was further diluted their DMSO or DMEM containing 10% FCS and containing 0,6 nm docetaxel. Then each of the diluted solutions were added to the wells of one of the tablets, which were made on 100 microlitres cells per well. The final concentration of docetaxel at this stage was 0.3 nm. Also in the case of the introduction of only one of the compounds according to the invention the concentration was 0,003, 0,01, 0,03, 0,1, 0,3, 1, 3 and 10 μm. The tablets additionally incubated at 37°C for three days in an atmosphere consisting of 95% air and 5% CO2. After incubation method WST-8 (H. Tominaga and other, Anal. Commun., 36, 47-50 (1999)) was measured cell growth. In this way WST-8 is the way, in which each well was added 20 microliters solution reagent WST-8, incubation was performed at 37°C for 60 minutes, the tablet is shaken and a colorimetric method to measure the quantity produced of formazane to determine the percentage of inhibition for medicines. Determined the effects of inhibition of cell growth caused by docetaxel and connection according to the invention, assuming a 0% value obtained in the processing of DMSO alone.

As can be seen from table 3, the connection according to the invention had excellent inhibitory effect on cell growth, as well as a synergistic effect with anticancer tool type taxane, such as docetaxel, in cancerous cells derived from human (HeLa S3).

48,9
Table 3
ExampleInhibitory effect on cell growth with the introduction of only one of docetaxel (0.3 nm)(%)The concentration of the compound in example (μm)Inhibitory effect on cell growth with the introduction of only one connection example (%)Inhibitory effect on cell growth when combined introduction of docetax the La and connection example (%)
Example 125,60,34,484,7
Example 353,40,3
1,0
5,4
26,9
74,1
90,4
Example 452,10,3
1,0
22,9
52,9
88,6
93,8
Example 552,10,3
1,0
7,2
25,6
70,0
of 87.0
Example 653,40,3
1,0
12,2
49,0
84,6
95,0
Example 753,41,0
3,0
37,1
59,0
91,8
95,0
Example 953,40,3
1,0
15,1
25,4
72,1
84,5
Example 1153,40,3
1,0
17,0
42,4
76,4
90,8
Example 1252,10,1
0,3
7,4
21,3
61,5
77,4
Example 1352,10,3
1,0
25,9
49,8
85,0
94,4
Example 1449,60,1
0,3
3.7V
36,0
71,5
87,4
Example 1549,60,1
0,3
0,5
25,4
72,8
of 87.8
Example 1649,60,3
1,0
11,8
18,2
67,3
88,5
Example 1749,60,1
0,3
11,3
39,9
79,0
92,9
Example 1852,10,1
0,3
28,3
53,4
81,2
92,0
Example 191,0
3,0
1,0
a 38.5
75,1
89,0
Example 2048,90,1
0,3
6,3
40,8
88,6
94,0
Example 2148,90,3
1,0
0,3
23,4
75,5
for 91.3
Example 2248,90,1
0,3
3,9
40,8
83,8
93,9
Example 2348,90,03
0,1
25,1
42,7
78,0
to 89.9
Example 2449,60,1
0,3
2,6
32,0
76,8
88,9

Based on the above data, it is assumed that the connection according to the invention should be applicable as anti-cancer agents, as it not only has excellent inhibitory activity against the growth of cells, based on the selective inhibitory activity against Aurora A, which also has a synergistic effect when combined application with other anticancer agent. Therefore, it is assumed that a pharmaceutical composition or a selective inhibitor of Aurora A, containing the new aminopyridine derivative according to the invention, or its pharmaceutically acceptable salt or ester, or an antitumor agent containing the compound according to the invention or its pharmaceutically acceptable salt or ester, is effective in the treatment of patients with cancer.

The aforementioned pharmaceutical composition and the inhibitor and the above-mentioned antitumor agent may contain a pharmaceutically acceptable carrier or diluent. In the present description, the term "pharmaceutically acceptable carrier or diluent" refers to excipients (for example, fats, waxes, semisolid and liquid polyols, natural or hydrogenated oils, etc); water (such as distilled water, particularly distilled water for injection and so on), physiological salt solution, alcohol (e.g. ethanol), glycerol, polyols, aqueous solution of glucose, mannitol, vegetable oils, etc); additives (for example, filler, dezintegriruetsja tool, binder, lubricant, moisturizing agent, stabilizer, emulsifier, dispersant additive, the preservative, sweetener, colorant, the means to improve the taste or flavor of a concentrating means is, the diluent, a buffer substance, the solvent or solubilizers tool, chemical substance to ensure the effect of storage, salts for modifying the osmotic pressure, means for coating or antioxidant), etc.

It is believed that examples of suitable tumor, which can be illustrated by therapeutic effect of the compounds according to the invention, is a solid cancer man. Examples of solid human cancer include brain cancer, head and neck cancer, esophageal cancer, thyroid cancer, small cell lung carcinoma, non-small cell lung carcinoma, breast cancer, stomach cancer, cancer of the gallbladder and bile duct, liver cancer, pancreatic cancer, cancer of the colon, colorectal cancer, ovarian cancer, horionepiteliome, uterine cancer, cervical cancer, cancer of the renal pelvis and ureter, bladder cancer, prostate cancer, penile cancer, testicular cancer, embryonal cancer, Wilms tumor, skin cancer, malignant melanoma, neuroblastoma, osteosarcoma, Ewing's sarcoma, soft tissue sarcoma, etc.

Next will be explained the above, the term "pharmaceutically acceptable salt or ester". When the connection according to the invention is used as antineoplastic or the like, it can also be applied in the form of pharmaceutically acceptable salts. Typical examples Pharm is citiesi acceptable salt include a salt of an alkali metal, such as sodium and potassium; salts of inorganic acids such as hydrochloride, sulfate, nitrate, phosphate, carbonate, bicarbonate, and ammonium salt of organic acid such as acetate, propionate, lactate, maleate, fumarate, tartt, malate, citrate, and ascorbate; salts of sulfonic acids, such as methanesulfonate, isothionate, bansilalpet and toluensulfonate; an acidic salt of the dibasic amino acids such as aspartate and glutamate; and other Pharmaceutically acceptable salt of the compound (I) preferably is a salt of an inorganic acid such as hydrochloride, sulfate, nitrate, phosphate, carbonate, bicarbonate and perchlorate; more preferably hydrochloride.

The way to obtain pharmaceutically acceptable salts of the compounds according to the invention can be realized by using an appropriate combination of those methods that are traditionally used in the field of organic synthetic chemistry. A specific example of such a method is a method in which a solution of the compounds according to the invention in its free form is subjected to titration to neutralize the alkali solution or an acid solution.

Examples of ester compounds according to the invention include methyl ester and complex ethyl ester. Such esters can be obtained by the esterification of the free carboxyl groups according to the traditional is nomu method.

With regard to each of the combined preparation according to the invention, it is possible to choose different forms of the drug, and such examples include preparations for oral administration such as tablets, capsules, powders, granules or liquids, or sterilized liquid preparations for parenteral administration such as solutions or suspensions, suppositories, ointments, etc.

Solid preparations can be obtained in the form of tablets, capsules, granules and powder without any additives or receive, using appropriate carriers (additives). Examples of such carriers (additives) may include saccharides such as lactose or glucose; corn, wheat or rice starch; fatty acids such as stearic acid; inorganic salts such as metallosindikat magnesium or anhydrous calcium phosphate; synthetic polymers such as polyvinylpyrrolidone or polyalkyleneglycol; alcohols, such as stearyl alcohol or benzyl alcohol; synthetic cellulose derivatives such as methylcellulose, carboxymethylcellulose, ethylcellulose or hypromellose; and other additives traditionally used, such as gelatin, talc, vegetable oils, and gum Arabic.

These solid preparations such as tablets, capsules, granules and powders can typically contain as the active ingredient, in the example, from 0.1 to 100% by weight and preferably from 5 to 98% by weight of compounds of the above formula (I), based on the total weight of the preparation.

Liquid preparations are produced in the form of suspension, syrup, injection and infusion through a drip (intravenous fluid), using appropriate additives, which are traditionally used in liquid preparations, such as water, alcohol or oil of vegetable origin, such as soybean oil, peanut oil and sesame oil.

In particular, when the drug is administered parenterally in the form of intramuscular injection, intravenous injection or subcutaneous injection, an appropriate solvent or diluent can be illustrated in the form of distilled water for injection, an aqueous solution of the hydrochloride lidocaine (for intramuscular injection), physiological saline, aqueous glucose solution, ethanol, polyethylene glycol, propylene glycol, liquid for intravenous injection (e.g., an aqueous solution of citric acid, sodium citrate and the like) or an electrolytic solution (for intravenous infusion through a drip and intravenous injection) or a mixed solution.

Such injection may be in the form of pre-prepared solution or in the form of powder as such powder or associated with a suitable carrier (additives is s) which dissolves during use. Liquid for injection may contain, for example, from 0.1 to 10% by weight of active ingredient, based on the total weight of the preparation.

Liquid preparations, such as suspension or syrup for oral administration may contain, for example, from 0.1 to 10% by weight of active ingredient, based on the total weight of the preparation.

Each drug in the combined preparation according to the invention can be obtained by the person skilled in the art according to conventional methods or well-known techniques. For example, a drug containing other anti-cancer agent, which is used in combination with the compound represented by the above General formula (I)may be obtained if the drug is a drug for oral administration, for example, by mixing the appropriate amount of anti-cancer agents with the appropriate amount of lactose and filling the mixture of hard gelatin capsules suitable for oral administration. On the other hand, obtaining can be done in case a product containing an antitumor agent, is an injection, for example, by mixing the appropriate amount of anti-cancer agents with the appropriate amount of 0.9%physiological saline races the thief and filling the mixture vials for injection.

Also in the case of a combined preparation containing the compound of the invention represented by the above General formula (I), and another anti-cancer agent, the person skilled in the art can easily obtain the product according to traditional methods or well-known methods.

In the method according to the invention preferred therapeutic dose may vary, for example, depending on the method of administration of the compounds represented by the General formula (I), the type compounds represented by the General formula (I), and dosage forms used compounds represented by the General formula (I); the type, route of administration and dosage forms other antineoplastic agents used in combination; and the type of cells being treated, the condition of the patient, etc. Optimal treatment in these conditions can be determined by a person skilled in the art, based on established traditional therapeutic dose and/or based on the content the present description of the invention.

In the method according to the invention, a therapeutic dose of a compound represented by the above General formula (I)may vary, especially depending on the type of connection type of the combined composition, frequency of application and the specific site to be treated, the severity of Soboleva what I the age of the patient, the doctor diagnosis, type of cancer or the like, However, as the typical recommendations, in the case of oral administration, the daily dose for an adult may be, for example, in the range from 1 to 1000 mg. In the case of parenteral administration, preferably intravenous administration, and more preferably intravenous infusion through a drip, the daily dose may be, for example, in the range from 1 to 100 mg/m2(the surface area). Here in the case of intravenous infusion through a drip introduction can be performed continuously, for example in a period of time from 1 to 48 hours. In addition, the frequency of injection can be changed depending on the method of introduction and symptoms, for example, from one to five times a day. Alternative with a particular method of introduction you can also use introduction after a certain period of time, such as the introduction through the day, the introduction of every two days or such other Period stop the introduction of the drug in the case of parenteral administration is, for example, from 1 to 6 weeks.

Although therapeutic dose of another anti-cancer agents used in combination with the compound represented by the General formula (I)is not specifically limited, if necessary, it can be determined by the person skilled in the art according to the WPI is local to the literature data. Examples could be the following.

Therapeutic dose of 5-fluorouracil (5-FU) is that, in the case of oral administration, for example, daily injected from 200 to 300 mg sequentially from one to three times a day, and in the case of injections, for example, by intravenous injection or intravenous infusion through a drip injected daily from 5 to 15 mg/kg / day during the first 5 days in a row and then by intravenous injection or intravenous infusion through a drip once a day injected from 5 to 7.5 mg/kg every other day (the dose can be appropriately increase or decrease).

Therapeutic dose of S-1 (Tegafur, Ginestet and Mod potassium) such that, for example, the initial dose (single dose) is determined on the basis of the standard amount depending on the surface area of the body, and it is administered orally twice a day after Breakfast and after lunch for 28 consecutive days, followed by cessation medications within 14 days. This corresponds to the rate of injection, which is repeated. The original standard quantity per unit area of the surface of the body (the equivalent of Tegafur) is 40 mg one introduction to the area of less than 1.25 m2; 50 mg one introduction to the area from 1.25 m2to area of less than 1.5 m2; 60 mg one introduction to the area of 1.5 m2or more. the shown dose appropriately increased or decreased depending on the condition of the patient.

Therapeutic dose of gemcitabine is, for example, 1 g of gemcitabine/m2for one, the introduction, which is administered by intravenous infusion through a drip for 30 minutes, and one infusion per week lasts for 3 weeks followed by a cessation medications during the fourth week. This corresponds to the rate of injection, which is repeated. This dose is appropriately reduced according to age, symptom or side effects.

Therapeutic dose of doxorubicin (e.g., doxorubicin hydrochloride), for example, is that in the case of intravenous injection once a day by intravenous single injection administered 10 mg (0.2 mg/kg) (titer) for 4-6 days in a row with subsequent cessation drugs within 7-10 days. This corresponds to the rate of injection, which is repeated two or three times. Here, the total dose is preferably 500 mg (titer)/m2(the surface area) or less, and can accordingly increase or decrease within the range.

Therapeutic dose of etoposide, for example, is that in the case of intravenous injection for 5 consecutive days is administered from 60 to 100 mg/m2(surface area) per day with subsequent prekrseni the m introduction medicinal product within three weeks, the dose can be appropriately increase or decrease). This corresponds to the rate of injection, which is repeated. However, in the case of oral administration, for example, for 5 consecutive days is administered from 175 to 200 mg / day with subsequent cessation drugs within three weeks, the dose can be appropriately increase or decrease). This corresponds to the rate of injection, which is repeated.

Therapeutic dose of docetaxel (docetaxel hydrate), for example, is that once a day by intravenous infusion through a drip administered 60 mg of docetaxel/m2(surface area) for 1 hour or more every 3 to 4 weeks (dose can be appropriately increase or decrease).

Therapeutic dose of paclitaxel, for example, is that once a day by intravenous infusion through a drip injected 210 mg/m2(surface area) for 3 hours, followed by cessation medications for at least 3 weeks. This corresponds to the rate of injection, which is repeated. The dose can be appropriately increase or decrease.

Therapeutic dose of cisplatin is that, in the case of intravenous injection once a day injected from 50 to 70 mg/m2(surface area), followed by the termination call is placed medicinal product for 3 weeks or more (the dose can be appropriately increase or decrease). This corresponds to the rate of injection, which is repeated.

Therapeutic dose carboplatin, for example, is that once a day by intravenous infusion through a drip injected from 300 to 400 mg/m2for 30 minutes or more with the subsequent cessation medications for at least 4 weeks (dose can be appropriately increase or decrease). This corresponds to the rate of injection, which is repeated.

Therapeutic dose oxaliplatin is that once a day by intravenous injection impose 85 mg/m2with subsequent cessation medications within two weeks. This corresponds to the rate of injection, which is repeated.

Therapeutic dose of irinotecan (e.g., irinotecan hydrochloride), for example, is that once a day by intravenous infusion through a drip administered 100 mg/m2for 3 or 4 doses with an interval of one week, followed by cessation medicines for at least two weeks.

Therapeutic dose of topotecan, for example, is that once a day by intravenous infusion through a drip administered 1.5 mg/m2for 5 days followed by a cessation medications during the less than the least 3 weeks.

Therapeutic dose of cyclophosphamide, for example, is that in the case of intravenous injection once a day by intravenous injection administered at 100 mg for several days in a row. If the patient can tolerate, the daily dose can be increased to 200 mg total dose, which can appropriately increase or decrease is from 3000 to 8000 mg If necessary, can be administered by intramuscular, intratracheally or intratumoral injection or infusion. On the other hand, in the case of oral administration, for example, injected daily from 100 to 200 mg.

therapeutic dose gefitinib is that, injected oral 250 mg once a day.

Therapeutic dose of cetuximab, for example, is that on the first day by intravenous infusion through a drip administered 400 mg/m2and then every week by intravenous infusion through a drip is administered at 250 mg/m2.

Therapeutic dose of bevacizumab, for example, is that each week by intravenous infusion through a drip administered 3 mg/kg

Therapeutic dose of trastuzumab, for example, is that adult initially injected once daily 4 mg trastuzumab/kg (body weight) followed by an intravenous infusion through a drip of 2 mg/kg over 90 minutes or more each the week with the second injection.

Therapeutic dose of eksemestana, for example, is that an adult orally administered 25 mg once daily after a meal.

Therapeutic dose leiprorelina (for example, acetate leiprorelina), for example, is that adult subcutaneously injected at 11.25 mg every 12 weeks.

Therapeutic dose of imatinib, for example, is that usually an adult in the chronic phase chronic myelogenous leukemia orally administered 400 mg once daily after a meal.

Therapeutic dose combination of 5-FU and leucovorin, for example, is that from the first day until the fifth day by intravenous infusion through a drip injected 425 mg/m25-FU 200 mg/m2leucovorin and repeat this course with an interval of 4 weeks.

Therapeutic dose of sorafenib, for example, such that two times a day orally administered 200 mg (400 mg daily)for at least 1 hour before eating or 2 hours after a meal.

Therapeutic dose of sunitinib, for example, is that, once daily orally administered 50 mg for four weeks, followed by the pass 2 weeks.

Experimental examples

In the examples and reference examples when conducting thin-layer chromatography was used silica gel Silica gel60F254(Merck) in the form of a plate, and the method of detection was used UV detec the op. As silica gel for the column used Biotage FLASH column (SI, NH). For the preparative liquid chromatography with reversed phase as columns used column XBridge Prep C18 (Waters), and mobile phase used a 0.1% aqueous solution triperoxonane acid and 0.1% solution triperoxonane acid in acetonitrile. MS spectra were measured using a Waters micromass ZQ2000 (ESI, ESCi). NMR spectra were measured with a spectrometer type JEOL JNM-AL400 (400 MHz) or Varian MERCURY400 (400 MHz), and all δ values are presented in ppm melting point was measured with increasing temperature at a rate of 1°C/min, using a combination of Mettler Toledo FP82HT Hot Stage and a NIKON Eclipse E600 POL.

Meanings of abbreviations the following.

s: singlet

d: doublet

DD: double doublet

t: triplet

dt: double triplet

kV: Quartet

Queen: quintet

m: multiplet

ush.: broadening

J: constant interaction

Hz: Hertz

DMSO-d6: dimethylsulfoxide-d6

TBS: tert-butyl(dimethyl)silyl group

MOM: methoxymethyl group

TBDPS: tert-butyl(diphenyl)silyl group

TsOH: p-toluensulfonate acid

SEM: (2-(trimethylsilyl)ethoxy)methyl group

Example 1

Synthesis of hydrochloride of TRANS-4-(3-chloro-2-pertenece)-1-((6-(1,3-thiazol-2-ylamino)pyridine-2-yl)methyl)cyclohexanecarboxylic acid

(1) Synthesis of 2-bromo-6(((tert-butyl(dimethyl)silyl)oxy)methyl)pyridine

To a solution of 10 g (6-bromopyridin-2-yl)methanol in 50 ml of N,N-dimethylformamide was sequentially added 4 g of imidazole and 8.4 g of tert-butyldimethylsilyloxy at room temperature, followed by stirring the reaction mixture at room temperature for 2 hours. After adding to the reaction mixture of water the mixture was extracted with n-hexane. The obtained hexane solution was dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated under vacuum, thus obtaining specified in the title compound as a colourless oil.

(2) Synthesis of 6-(((tert-butyl(dimethyl)silyl)oxy)methyl)-N-((2Z)-3-(methoxymethyl)-1,3-thiazol-2(3H)-ilidene)pyridine-2-amine

The mixture 15,92 g of 2-bromo-6-(((tert-butyl(dimethyl)silyl)oxy)methyl)pyridine, 5.53 g of 2-aminothiazole, totaling 3.04 g of 9,9-dimethyl-4,5-bis(diphenylphosphino)xanthene, 2,72 g of the complex Tris(dibenzylideneacetone)dipalladium(0)-chloroform, 18,86 g of cesium carbonate and 100 ml of toluene was stirred at 120°C overnight and then cooled to room temperature and was filtered, the insoluble substance by using celite. The obtained toluene solution was washed with water. The organic layer was dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated under vacuum, thus obtaining the raw (untreated) product.

Ready is whether the suspension obtained crude (crude) product in 100 ml of chloroform, and then, with ice cooling sequentially added to 13.7 ml of N,N-diisopropylethylamine and 4.8 ml of a simple chloromethylmethylether ether, followed by stirring the reaction mixture at room temperature over night. The chloroform was removed in vacuo and to the residue was added water, followed by extraction with ethyl acetate. Received an ethyl acetate solution was dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated in vacuum. The obtained residue was purified by column chromatography on silica gel (eluent: hexane to a mixture of hexane/ethyl acetate = 5/1), while receiving specified in the title compound as a pale yellow solid.

(3) Synthesis of (6-(((2Z)-3-(methoxymethyl)-1,3-thiazol-2(3H)-ilidene)amino)pyridin-2-yl)methanol

To a solution of 14.28 g of 6-(((tert-butyl(dimethyl)silyl)oxy)methyl)-N-((2Z)-3-(methoxymethyl)-1,3-thiazol-2(3H)-ilidene)pyridine-2-amine in 30 ml of chloroform and 30 ml of methanol was added 30 ml triperoxonane acid under ice cooling, followed by stirring the reaction mixture at room temperature over night. The reaction mixture was evaporated in vacuum. The obtained residue was neutralized with saturated aqueous sodium bicarbonate solution and was extracted with ethyl acetate. Received an ethyl acetate solution was dried over anhydrous magnesium sulfate and filtration is ovale. The filtrate was concentrated in vacuum. The obtained residue was purified by column chromatography on silica gel (eluent: hexane to a mixture of hexane/ethyl acetate = 1/1), while receiving specified in the title compound as a pale yellow solid.

(4) Synthesis of 6-(methyl bromide)-N-((2Z)-3-(methoxymethyl)-1,3-thiazol-2(3H)-ilidene)pyridine-2-amine

To a solution 4,43 g (6-(((2Z)-3-(methoxymethyl)-1,3-thiazol-2(3H)-ilidene)amino)pyridin-2-yl)methanol in 40 ml of tetrahydrofuran was sequentially added 3.2 ml of triethylamine and 1.5 ml of methylsulfonylamino under ice cooling, followed by stirring the reaction mixture at room temperature for 1 hour. At room temperature was sequentially added to 0.74 ml of triethylamine and 0.27 ml of methylsulfonylamino, followed by stirring the reaction mixture at room temperature for 1 hour. The precipitate was filtered, washed with tetrahydrofuran and then the filtrate was concentrated in vacuum. To a solution of the obtained residue in 30 ml of N,N-dimethylformamide was added 4,58 g of lithium bromide under ice cooling, followed by stirring the reaction mixture at room temperature over night. To the reaction mixture was added water and was extracted with ethyl acetate. Received an ethyl acetate solution is then washed with water and saturated the salt solution, was dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated in vacuum. The obtained residue was purified by column chromatography on silica gel (eluent: chloroform to the mixture of chloroform/ethyl acetate = 10/1), while receiving specified in the title compound as a pale yellow solid.

(5) Synthesis of tert-butyl CIS-4-((tert-butyl(diphenyl)silyl)oxy)-1-((6-(((2Z)-3-(methoxymethyl)-1,3-thiazol-2(3H)-ilidene)amino)pyridin-2-yl)methyl)cyclohexanecarboxylate

To a solution of 3.8 ml of Diisopropylamine in tetrahydrofuran was added to 17.3 ml of a hexane solution containing 1,58M n-utility under ice cooling, followed by stirring the reaction mixture for 30 minutes. After cooling to -78°C the solution was added 12 g of tert-butyl 4-((tert-butyl(diphenyl)silyl)oxy)cyclohexanecarboxylate obtained by the reference 1, in 30 ml of tetrahydrofuran and the resulting solution was stirred for 2 hours at -78°C. To the reaction mixture solution was added 2,87 g of 6-(methyl bromide)-N-((2Z)-3-(methoxymethyl)-1,3-thiazol-2(3H)-ilidene)pyridine-2-amine and 7.9 ml hexamethylphosphoramide in 20 ml tetrahydrofuran (THF), followed by a gradual heating of the reaction mixture to room temperature. The reaction mixture was stirred at room temperature overnight. To the reaction mixture were added saturated in the hydrated solution of ammonium chloride followed by extraction with ethyl acetate. Received an ethyl acetate layer was washed with saturated salt solution, dried over anhydrous magnesium sulfate, was filtered. The filtrate was concentrated in vacuum. The obtained residue was purified by column chromatography on silica gel (eluent: hexane to a mixture of hexane/ethyl acetate = 10/1-4/1), while receiving specified in the title compound as a pale yellow oil.

(6) Synthesis of tert-butyl CIS-4-hydroxy-1-((6-(((2Z)-3-(methoxymethyl)-1,3-thiazol-2(3H)-ilidene)amino)pyridin-2-yl)methyl)cyclohexanecarboxylate

The solution to 5.56 g of tert-butyl CIS-4-((tert-butyl(diphenyl)silyl)oxy)-1-((6-(((2Z)-3-(methoxymethyl)-1,3-thiazol-2(3H)-ilidene)amino)pyridin-2-yl)methyl)cyclohexanecarboxylate in 100 ml of tetrahydrofuran was added 49,6 ml of 1M solution of tetrabutylammonium fluoride in tetrahydrofuran at room temperature, followed by stirring the reaction mixture at 60°C over night. The reaction mixture was cooled to room temperature, followed by dilution with ethyl acetate. The resulting solution was sequentially washed with a solution of phosphate buffer pH 6.8 and saturated salt solution, dried over anhydrous magnesium sulfate, was filtered. The filtrate was concentrated in vacuum. The obtained residue was purified by column chromatography on silica gel (eluent: hexane to a mixture of hexane/ethyl acetate = 1/), while receiving specified in the title compound as a pale yellow oil.

(7) Synthesis of tert-butyl TRANS-4-(3-chloro-2-pertenece)-1-((6-(((2Z)-3-(methoxymethyl)-1,3-thiazol-2(3H)-ilidene)amino)pyridin-2-yl)methyl)cyclohexanecarboxylate

To a solution of a mixture of 4,34 g of tert-butyl CIS-4-hydroxy-1-((6-(((2Z)-3-(methoxymethyl)-1,3-thiazol-2(3H)-ilidene)amino)pyridin-2-yl)methyl)cyclohexanecarboxylate, of 2.93 g of 3-chloro-2-terfenol and of 5.24 g of triphenylphosphine in 70 ml of tetrahydrofuran was added 3,94 ml of diisopropylcarbodiimide under ice cooling, followed by stirring the reaction mixture at room temperature for 1 hour. To the reaction mixture was added water and was extracted with ethyl acetate. Received an ethyl acetate layer was washed with saturated salt solution, dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated in vacuum. The obtained residue was purified by column chromatography on silica gel (eluent: hexane to a mixture of hexane/ethyl acetate = 3/1), while receiving specified in the title compound as a pale yellow oil.

(8) Synthesis of hydrochloride of TRANS-4-(3-chloro-2-pertenece)-1-(6-(1,3-thiazol-2-ylamino)pyridine-2-yl)methyl)cyclohexanecarboxylic acid

To a 3.9 g of tert-butyl TRANS-4-(3-chloro-2-pertenece)-1-((6-(((2Z)-3-(methoxymethyl)-1,-thiazol-2(3H)-ilidene)amino)pyridin-2-yl)methyl)cyclohexanecarboxylate was added 100 ml of a 4M solution of hydrogen chloride in 1,4-dioxane, followed by stirring the reaction mixture at 90°C for 5 hours. After cooling the reaction mixture to room temperature, to the mixture was added 100 ml of a simple tert-butyl methyl ether. The precipitate was collected by filtration and washed simple tert-butylmethylamine ether, thus obtaining a colorless solid.

The obtained colorless solid was dissolved in 1.2 l of ethanol at 80°C. the Ethanol was removed by distillation to reduce the volume of the solution to approximately one third. The resulting solution was cooled to room temperature, followed by stirring at room temperature over night. The obtained solid substance was collected by filtration and washed with chilled ethanol, thus obtaining specified in the title compound as a colourless crystalline substance.

1H-NMR (DMSO-d6) δ: 1.60-to of 1.92 (8H, m), 3,03 (2H, c), to 4.62 (1H, users), of 6.90 (1H, d, J=7,4 Hz), 7,05-7,22 (5H, m), 7,53 (1H, d, J=4,1 Hz), 7,74 (1H, t, J=7,8 Hz).

Mass: 462,464 (M+1)+

Example 2

Synthesis of TRANS-4-(3-chloro-2-pertenece)-1-(6-(1,3-thiazol-2-ylamino)pyridine-2-yl)methyl)cyclohexanecarboxylic acid

The way A

To 47,9 mg of hydrochloride of TRANS-4-(3-chloro-2-pertenece)-1-(6-(1,3-thiazol-2-ylamino)pyridine-2-yl)methyl)cyclohexanecarboxylic acid obtained in example 1, was sequentially added 4 ml of water and 4 ml of ethanol, followed by stirring the reaction is Oh mixture at room temperature for 12 hours. The precipitate was collected by filtration and washed with water, thus obtaining specified in the title compound in the form of colorless needle-like crystals (TPL: 202-222°C).

1H-NMR (DMSO-d6) δ: 1.60-to of 1.92 (8H, m), 2,98 (2H, c), br4.61 (1H, users), of 6.71 (1H, d, J=7,2 Hz), make 6.90 (1H, d, J=8,2 Hz), 6,98 (1H, d, J=3.5 Hz), 7,10-7,22 (3H, m), 7,38 (1H, d, J=3.5 Hz), 7,60 (1H, t, J=7,6 Hz).

Mass: 462,464 (M+1)+

Method B

To 460 mg of the hydrochloride of TRANS-4-(3-chloro-2-pertenece)-1-(6-(1,3-thiazol-2-ylamino)pyridine-2-yl)methyl)cyclohexanecarboxylic acid obtained in example 1, was sequentially added 40 ml water and 40 ml of ethanol, followed by stirring the reaction mixture at room temperature for 4 days. The precipitate was collected by filtration and washed with water, thus obtaining specified in the title compound as colourless plates (TPL: 224-242°C).

1H-NMR (DMSO-d6) δ: 1.60-to of 1.92 (8H, m), 2,98 (2H, c), br4.61 (1H, users), of 6.71 (1H, d, J=7,2 Hz), make 6.90 (1H, d, J=8,2 Hz), 6,98 (1H, d, J=3.5 Hz), 7,10-7,22 (3H, m), 7,38 (1H, d, J=3.5 Hz), 7,60 (1H, t, J=7,6 Hz).

Mass: 462,464 (M+1)+

Example 3

Synthesis of hydrochloride of TRANS-4-(2,3-divergence)-1-((6-(1,3-thiazol-2-ylamino)pyridine-2-yl)methyl)cyclohexanecarboxylic acid

Specified in the title compound was obtained as a white solid according to example 1 using 2,3-diferena instead of 3-chloro-2-terfenol that PR is changed in stage 1(7) of example 1.

1H-NMR (DMSO-d6) δ: 1.60-to of 1.92 (8H, m), to 3.02 (2H, c), to 4.62 (1H, users), at 6.84 (1H, d, J=8,4 Hz), 6,97-to 7.15 (5H, m), 7,49 (1H, d, J=3,7 Hz), of 7.70 (1H, t, J=7,8 Hz).

Mass: 446 (M+1)+

Example 4

Synthesis of hydrochloride of TRANS-4-(2-fluoro-3-(trifluoromethyl)phenoxy)-1-((6-(1,3-thiazol-2-ylamino)pyridine-2-yl)methyl)cyclohexanecarboxylic acid

Specified in the title compound was obtained as a white solid according to example 1, using 2-fluoro-3-(trifluoromethyl)phenol instead of 3-chloro-2-terfenol, which was used in stage 1(7) of example 1.

1H-NMR (DMSO-d6) δ: 1,62-of 1.95 (8H, m), 3,03 (2H, c), and 4.68 (1H, users), 6,89 (1H, d, J=7,2 Hz), 7,07 (1H, d, J=8,4 Hz), to 7.15 (1H, d, J=3,7 Hz), 7,28-to 7.35 (2H, m), 7,52 (1H, d, J=3,7 Hz), 7,56 (1H, t, J=6.8 Hz), 7,73 (1H, t, J=7,8 Hz).

mass: 496 (M+1)+

Example 5

Synthesis of hydrochloride of TRANS-4-(2,3-dichlorophenoxy)-1-((6-(1,3-thiazol-2-ylamino)pyridine-2-yl)methyl)cyclohexanecarboxylic acid

Specified in the title compound was obtained as a white solid according to example 1 using 2,3-dichlorophenol instead of 3-chloro-2-terfenol, which was used in stage 1(7) of example 1.

1H-NMR (DMSO-d6) δ: 1,51-of 1.66 (2H, m), 1,69-1,89 (6H, m), of 2.97 (2H, c), 4,72 (1H, users), 6,75-6,85 (1H, m), 6,95-7,10 (2H, m), 7,10-7,16 (2H, m), 7,25 (1H, t, J=8,2 Hz), 7,42-7,49 (1H, m), 7,62-7,72 (1H, m).

mass: 478,480 (M+1)+

Example 6

Synthesis of TRANS-4-(3-chloro-2-pertenece)-1-((6(1,3-thiazol-2-ylamino)pyridine-2-yl)methyl)cyclohexanecarboxylic

To a solution of 20 mg of the hydrochloride of TRANS-4-(3-chloro-2-pertenece)-1-((6-(1,3-thiazol-2-ylamino)pyridine-2-yl)methyl)cyclohexanecarboxylic acid obtained in example 1 in 3 ml of chloroform at room temperature was sequentially added 21 mg of ammonium chloride, 0,056 ml of triethylamine, 31 mg of hydroxybenzotriazole hydrate and 38 mg of the hydrochloride of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide, followed by stirring the reaction mixture at room temperature over night. After adding to the reaction mixture, saturated aqueous sodium bicarbonate solution, the mixture was extracted with ethyl acetate. Received an ethyl acetate solution was dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated in vacuum. The obtained residue was purified using preparative thin-layer chromatography (KieselgelTM60F254, Art5744 (Merck), chloroform/methanol = 10/1), while receiving specified in the title compound as a white solid.

1H-NMR (DMSO-d6) δ: 1,63-of 1.93 (8H, m), of 2.92 (2H, c), 4,55 (1H, user. c)of 6.68 (1H, d, J=7,4 Hz), 6,85 (1H, d, J=8,4 Hz)6,94 (2H, d, J=3.1 Hz), 7,05-7,20 (3H, m), 7,25 (1H, c), 7,35 (1H, d, J=3.5 Hz), 7,55 (1H, t, J=7.8 Hz), 11,13 (1H, c).

mass: 461,463 (M+1)+

Example 7

Synthesis of triptoreline TRANS-4-(2-fluoro-3-(trifluoromethyl)phenoxy)-1-((6-(1H-pyrazole-3-ylamino)pyridine-2-yl)methyl)cyclohexanecarboxylic acids is

(1) Synthesis of 2-bromo-6-(methyl bromide)pyridine

To a solution of 498 mg (6-bromopyridin-2-yl)methanol 6 ml of N,N - dimethylformamide under ice cooling sequentially added to 1.15 ml of diisopropylethylamine and a solution of 695 mg methanesulfonamido anhydride in 2 ml of N,N-dimethylformamide, followed by stirring the reaction mixture at room temperature for 20 minutes. Then to the solution was added 693 mg of lithium bromide, followed by stirring the reaction mixture at room temperature for 1 hour. After adding to the reaction mixture, saturated aqueous sodium bicarbonate solution, the mixture was extracted with ethyl acetate. Received an ethyl acetate solution was dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated in vacuum. The obtained residue was purified by column chromatography on silica gel (eluent: hexane/ethyl acetate = 20/1-3/2), while receiving specified in the title compound as a pale yellow solid.

(2) Synthesis of tert-butyl CIS-1-((6-bromopyridin-2-yl)methyl)-4-((tert-butyl(diphenyl)silyl)oxy)cyclohexanecarboxylate

To a solution of 0.82 ml of Diisopropylamine in 20 ml of tetrahydrofuran under ice cooling was added to 3.7 ml of a hexane solution containing 1,58M n-utility, with the settlement of edusim by stirring the reaction mixture for 30 minutes. After cooling the reaction mixture to -78°C the solution was added a solution of 2.67 g of tert-butyl 4-((tert-butyl(diphenyl)silyl)oxy)cyclohexanecarboxylate obtained by the reference 1, in 10 ml of tetrahydrofuran and the resulting solution was stirred for 1 hour at -78°C. To the reaction mixture was added a solution of 980 mg of 2-bromo-6-(methyl bromide)pyridine and 2.7 ml hexamethylphosphoramide in 5 ml of tetrahydrofuran, followed by a gradual heating of the reaction mixture to room temperature and then stirred the reaction mixture at room temperature over night. To the reaction mixture were added saturated aqueous solution of ammonium chloride followed by extraction with chloroform. The obtained chloroform solution was dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated in vacuum. The obtained residue was purified by column chromatography on silica gel (eluent: hexane/ethyl acetate = 100/1-9/1), while receiving specified in the title compound as a pale yellow oil.

(3) Synthesis of tert-butyl CIS-1-((6-bromopyridin-2-yl)methyl)-4-hydroxycyclohexanecarboxylate

To a solution of 1.6 g of tert-butyl CIS-1-((6-bromopyridin-2-yl)methyl)-4-((tert-butyl(diphenyl)silyl)oxy)cyclohexanecarboxylate in 30 ml of tetrahydrofuran at room temperature was added 16 ml of tertrahydrofuran ring solution, terasawa 1M tetrabutylammonium fluoride, followed by stirring the reaction mixture at 60°C over night. The reaction mixture was cooled to room temperature, followed by dilution with chloroform. The resulting solution was sequentially washed with a solution of phosphate buffer pH 6.8 and saturated salt solution, dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated in vacuum. The obtained residue was purified by column chromatography on silica gel (eluent: a mixture of hexane/ethyl acetate = 8/1 to ethyl acetate), obtaining mentioned in the title compound as a pale yellow solid.

(4) Synthesis of tert-butyl TRANS-1-((6-bromopyridin-2-yl)methyl)-4-(2-fluoro-3-(trifluoromethyl)phenoxy)cyclohexanecarboxylate

To a solution of 150 mg of tert-butyl CIS-1-((6-bromopyridin-2-yl)methyl)-4-hydroxycyclohexanecarboxylate, 219 mg of 2-fluoro-3-(trifluoromethyl)phenol and 320 mg of triphenylphosphine in 2.5 ml of tetrahydrofuran under ice cooling was added to 0.24 ml of diisopropylcarbodiimide, followed by stirring the reaction mixture at room temperature for 15 minutes. The reaction mixture was concentrated in vacuo and purify the resulting residue using column chromatography on silica gel (eluent: hexane/ethyl acetate = 50/1-4/1), while receiving specified in the title compound as pale as the addition of oil.

(5) Synthesis of tert-butyl TRANS-1-((6-((1-tert-butyl-1H-pyrazole-5-yl)amino)pyridin-2-yl)methyl)-4-(2-fluoro-3-(trifluoromethyl)phenoxy)cyclohexanecarboxylate

A mixture of 140 mg of tert-butyl TRANS-1-((6-bromopyridin-2-yl)methyl)-4-(2-fluoro-3-(trifluoromethyl)phenoxy)cyclohexanecarboxylate, 102 mg of 1-tert-butyl-1H-pyrazole-5-amine-n-toluensulfonate received the link 4, and 25.4 mg of 9,9-dimethyl-4,5-bis(diphenylphosphino)xanthene, to 21.6 mg of the complex Tris(dibenzylideneacetone)dipalladium(0)-chloroform, 139 mg of potassium phosphate and 4 ml of 1,4-dioxane was stirred at 100°C overnight and then cooled to room temperature. The insoluble substance was filtered using celite and washed with ethyl acetate. Received an ethyl acetate solution was washed with water, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuum. The obtained residue was purified by column chromatography on silica gel (eluent: hexane/ethyl acetate = 20/1-3/2), while receiving specified in the title compound as a pale yellow oil.

(6) Synthesis of triptoreline TRANS-4-(2-fluoro-3-(trifluoromethyl)phenoxy)-1-((6-(1H-pyrazole-3-ylamino)pyridine-2-yl)methyl)cyclohexanecarboxylic acid

The solution 88,8 mg of tert-butyl TRANS-1-((6-((1-tert-butyl-1H-pyrazole-5-yl)amino)pyridin-2-yl)methyl)-4-(2-fluoro-3-(trif ormetal)phenoxy)cyclohexanecarboxylate in 1 ml of formic acid was stirred at 110°C for 1 hour. The reaction mixture was cooled to room temperature, followed by concentration in vacuo. The obtained residue was purified using preparative liquid chromatography with reversed phase with the subsequent concentration of the fractions obtained in vacuum, thus obtaining specified in the title compound as a pale yellow solid.

1H-NMR (CD3OD) δ: 1,82-2,17 (8H, m), 3,24 (2H, c), 4,70 (1H, c), 6,18 (1H, d, J=2,8 Hz), 7,05 (1H, d, J=7,2 Hz), 7,19-7,31 (3H, m), 7,45 (1H, dt, J=8,4, 2,8 Hz), 7,78 (1H, d, J=2.4 Hz), of 8.06 (1H, DD, J=8,8, 7,2 Hz).

mass: 479 (M+1)+

Example 8

Synthesis of triptoreline TRANS-4-(3-chloro-2-pertenece)-1-((6-(1H-pyrazole-3-ylamino)pyridine-2-yl)methyl)cyclohexanecarboxylic acid

Specified in the title compound was obtained as a white solid according to example 7, using 3-chloro-2-terfenol instead of 2-fluoro-3-(trifluoromethyl)phenol, which was used to stage 7(4) of example 7.

1H-NMR (CD3OD) δ: 1,79-of 2.15 (8H, m), 3,20 (2H, c), to 4.62 (1H, c), 6,18 (1H, d, J=2.4 Hz), 7,01-to 7.15 (4H, m), 7,20 (1H, d, J=8,8 Hz), 7,79 (1H, d, J=2.4 Hz), of 8.04 (1H, DD, J=8,8, 7,2 Hz).

mass: 445,447 (M+1)+

Example 9

Synthesis of TRANS-4-(3-chloro-2-pertenece)-1-((6-(1H-pyrazole-3-ylamino)pyridine-2-yl)methyl)cyclohexanecarboxylic

To a solution of 32.1 mg trifenatate TRANS-4-(3-chloro-2-pertenece)-1-((6-(1H-pyrazole-3-ylamino)the feast of the DIN-2-yl)methyl)cyclohexanecarboxylic acid, obtained according to example 8, in 1 ml of dimethyl sulfoxide at room temperature was sequentially added 7.5 mg of ammonium chloride, 0,038 ml of triethylamine, 20.2 mg of hydroxybenzotriazole hydrate, and 24.6 mg of the hydrochloride of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide, followed by stirring the reaction mixture at room temperature over night. The reaction mixture was purified using preparative liquid chromatography with reversed phase and then using preparative thin-layer chromatography (NH-PLC05 (FUJI SILYSIA CHEMICAL), chloroform/methanol = 20/1), while receiving specified in the title compound as a white solid.

1H-NMR (CD3OD) δ: 1,82 is 2.00 (8H, m),3.04 from (2H, c), 4,55 (1H, c), of 5.75 (1H, users), 6,60-to 6.80 (2H, m), 7,00-7,10 (3H, m), 7,44 (1H, users), to 7.50 (1H, t, J=8.0 Hz).

mass: 444,446 (M+1)+

Example 10

Synthesis of triptoreline TRANS-4-(3-chloro-2-pertenece)-1-((6-(1H-pyrazole-3-ylamino)pyrazin-2-yl)methyl)cyclohexanecarboxylic acid

(1) Synthesis of N-(1-tert-butyl-1H-pyrazole-5-yl)-6-chloropyrazine-2-amine

The mixture to 60.6 g of 2,6-dichloropyrazine, 62,2 g of 1-tert-butyl-1H-pyrazole-5-amine obtained in reference 3, with 23.5 g of 9,9-dimethyl-4,5-bis(diphenylphosphino)xanthene, 21,0 g of the complex Tris(dibenzylideneacetone)dipalladium(0)-chloroform, to 172.6 g of potassium phosphate and 1,17 l of 1,4-dioxane was stirred at 100 the C overnight and then cooled to room temperature. The insoluble substance was filtered using celite and washed with ethyl acetate. Received an ethyl acetate solution was washed with water and saturated salt solution, dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated in vacuum. The obtained residue was purified by column chromatography on silica gel (eluent: hexane/ethyl acetate = 4/1-2/1), while receiving specified in the title compound as a yellow solid.

(2) Synthesis of N-(1-tert-butyl-1H-pyrazole-5-yl)-6-vinylpyridin-2-amine

A mixture consisting of 65,04 g of N-(1-tert-butyl-1H-pyrazole-5-yl)-6-chloropyrazine-2-amine, to 41.6 g of vinyltrifluoroborate potassium, 4,22 g complex (1,1'-bis(diphenylphosphino)ferrocene)dichloropalladium(II) in dichloromethane, 72 ml of triethylamine and 685 ml of 1-propanol was stirred at 110°C overnight and then cooled to room temperature and concentrated in vacuum. The obtained residue was diluted with ethyl acetate and was filtered, the insoluble substance by using celite. Received an ethyl acetate solution was washed with water, dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated in vacuum. From the obtained residue was preparing a suspension in 100 ml of ethyl acetate and added to a mixture of 400 ml simple diisopropyl ether. The precipitate was collected, thus obtaining pointed to by the e in the title compound as a pale brown solid.

(3) Synthesis of 6-((1-tert-butyl-1H-pyrazole-5-yl)amino)pyrazin-2-carbaldehyde

To a solution of 56,36 g of N-(1-tert-butyl-1H-pyrazole-5-yl)-6-vinylpyridin-2-amine in 570 ml of acetonitrile at room temperature was sequentially added 48,9 g N-oxide N-methylmorpholine and 215 ml 0,1M aqueous solution of osmium tetroxide, followed by stirring the reaction mixture at room temperature over night. After adding to the reaction mixture of 73 g of sodium sulfite and 580 ml of water the mixture was extracted with ethyl acetate. Received an ethyl acetate solution was washed with saturated salt solution, dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated under vacuum, thus obtaining the raw (untreated) product.

To a solution of the obtained residue in 572 ml of acetonitrile and 858 ml of water under ice cooling was added 62.8 g of periodate sodium, followed by stirring the reaction mixture at room temperature for 3 hours. The reaction mixture was diluted with water and extracted with ethyl acetate. Received an ethyl acetate solution was washed with saturated salt solution, dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated in vacuum. The obtained residue was purified by column chromatography on silica gel (eluent: chloroform to the mixture chloroform/methanol = 20/1)to give p and this is mentioned in the title compound as a dark brown oil.

(4) Synthesis of (6-((1-tert-butyl-1H-pyrazole-5-yl)amino)pyrazin-2-yl)methanol

To a solution 14,99 g of 6-((1-tert-butyl-1H-pyrazole-5-yl)amino)pyrazin-2-carbaldehyde in 235 ml of ethanol under ice cooling was added 2,31 g of sodium borohydride, followed by stirring the reaction mixture for 1 hour. After slowly added to the reaction mixture under ice cooling 61 ml of 1M hydrochloric acid ethanol drove in a vacuum. The obtained residue was diluted with water and was extracted with chloroform. The obtained chloroform solution was washed with saturated salt solution, dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated in vacuum. The obtained residue was purified by column chromatography on silica gel (eluent: chloroform to the mixture chloroform/methanol = 20/1), while receiving specified in the title compound as a brown solid.

(5) Synthesis of N-(1-tert-butyl-1H-pyrazole-5-yl)-6-(chloromethyl)pyrazin-2-amine

To a solution of 507,3 mg (6-((1-tert-butyl-1H-pyrazole-5-yl)amino)pyrazin-2-yl)methanol in 6.8 ml of chloroform under cooling with ice consistently added 1.08 ml diisopropylethylamine and 0.24 ml of methylsulfonylamino, followed by stirring the reaction mixture at room temperature for 1.5 hours. To react the Onna mixture was sequentially added byr442.9 mg of lithium chloride and 6.8 ml of N,N-dimethylformamide, followed by stirring the reaction mixture at room temperature for 2 hours. After diluting the reaction mixture with ethyl acetate, an ethyl acetate solution is then washed with water and saturated salt solution, dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated in vacuum. The obtained residue was purified by column chromatography on silica gel (eluent: hexane/ethyl acetate = 20/1-1/4), while receiving specified in the title compound as a yellow solid.

(6) Synthesis of tert-butyl CIS-4-((tert-butyl(diphenyl)silyl)oxy)-1-((6-((1-tert-butyl-1H-pyrazole-5-yl)amino)pyrazin-2-yl)methyl)cyclohexanecarboxylate

To a solution of 0.15 ml of Diisopropylamine 4.2 ml of tetrahydrofuran under ice cooling was added 0.7 ml of hexane solution containing 1,58 M n-utility, followed by stirring the reaction mixture for 30 minutes. After cooling to -78°C the solution was added a solution of 488 mg of tert-butyl 4-((tert-butyl(diphenyl)silyl)oxy)cyclohexanecarboxylate obtained by the reference 1, in 2 ml of tetrahydrofuran. The resulting solution was stirred for 1 hour at -78°C. To the reaction mixture was added a solution of 115 mg of N-(1-tert-butyl-1H-pyrazole-5-yl)-6-(chloromethyl)pyrazin-2-amine and 0.5 ml hexamethylphosphoramide in 1.5 ml of tetrahydrofuran, followed by a gradual heating of the reaction mixture to room temperature. The reaction mixture is displaced is ivali at room temperature over night. To the reaction mixture were added saturated aqueous solution of ammonium chloride followed by extraction with chloroform. The obtained chloroform solution was dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated in vacuum. The obtained residue was purified by column chromatography on silica gel (eluent: hexane to a mixture of hexane/ethyl acetate = 1/4), while receiving specified in the title compound as a yellow oil.

(7) Synthesis of tert-butyl CIS-1-((6-((1-tert-butyl-1H-pyrazole-5-yl)amino)pyrazin-2-yl)methyl)-4-hydroxycyclohexanecarboxylate

To a solution of 60.5 mg of tert-butyl CIS-4-((tert-butyl(diphenyl)silyl)oxy)-1-((6-((1-tert-butyl-1H-pyrazole-5-yl)amino)pyrazin-2-yl)methyl)cyclohexanecarboxylate in 1 ml of tetrahydrofuran at room temperature was added 0,36 ml tertrahydrofuran ring of a solution containing 1M tetrabutylammonium fluoride, followed by stirring the reaction mixture at 60°C over night. The reaction mixture was cooled to room temperature, followed by dilution with chloroform. The resulting solution was sequentially washed with a solution of phosphate buffer pH 6.8 and saturated salt solution, dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated in vacuum. The obtained residue was purified by column chromatography naselesele (eluent: chloroform/methanol = 50/1-4/1), while receiving specified in the title compound as a yellow oil.

(8) Synthesis of tert-butyl TRANS-1-((6-((1-tert-butyl-1H-pyrazole-5-yl)amino)pyrazin-2-yl)methyl)-4-(3-chloro-2-pertenece)cyclohexanecarboxylate

To a solution of 28.9 mg of tert-butyl CIS-1-((6-((1-tert-butyl-1H-pyrazole-5-yl)amino)pyrazin-2-yl)methyl)-4-hydroxycyclohexanecarboxylate, 30 mg of 3-chloro-2-terfenol and 52.2 mg of triphenylphosphine in 0.5 ml of tetrahydrofuran under ice cooling was added 0.04 ml of diisopropylcarbodiimide, followed by stirring the reaction mixture at room temperature over night. The reaction mixture was concentrated in vacuo and the resulting residue was purified using preparative thin-layer chromatography (NH-PLC05 (FUJI SILYSIA CHEMICAL), hexane/ethyl acetate = 1/1), while receiving specified in the title compound as a yellow oil.

(9) Synthesis of triptoreline TRANS-4-(3-chloro-2-pertenece)-1-((6-(1H-pyrazole-3-ylamino)pyrazin-2-yl)methyl)cyclohexanecarboxylic acid

A solution of 16.2 mg of tert-butyl TRANS-1-((6-((1-tert-butyl-1H-pyrazole-5-yl)amino)pyrazin-2-yl)methyl)-4-(3-chloro-2-pertenece)cyclohexanecarboxylate in 0.5 ml of formic acid was stirred at 100°C for 1.5 hours. The reaction mixture was cooled to room temperature, followed by concentration in vacuo. Received the STATCOM was purified using preparative liquid chromatography with reversed phase with the subsequent concentration of the fractions obtained in vacuum, while receiving specified in the title compound as a pale yellow solid.

1H-NMR (CD3OD) δ: 1,75-2,04 (8H, m), 3,05 (2H, c), 4,53-4,59 (1H, m), to 6.39 (1H, d, J=2.4 Hz), 6,98-to 7.09 (3H, m), a 7.62 (1H, d, J=2.4 Hz), to 7.84 (1H, c), 8,17 (1H, c).

mass: 446,448 (M+1)+

Example 11

Synthesis of TRANS-4-(3-chloro-2-pertenece)-1-((6-(1H-pyrazole-3-ylamino)pyrazin-2-yl)methyl)cyclohexanecarboxylic

Specified in the title compound was obtained as a pale yellow solid according to example 9, using triptorelin TRANS-4-(3-chloro-2-pertenece)-1-((6-(1H-pyrazole-3-ylamino)pyrazin-2-yl)methyl)cyclohexanecarboxylic acid, which was obtained in example 10, instead of triptoreline TRANS-4-(3-chloro-2-pertenece)-1-((6-(1H-pyrazole-3-ylamino)pyridine-2-yl)methyl)cyclohexanecarboxylic acid, which was used in example 9.

1H-NMR (DMSO-d6) δ: 1,62-of 1.93 (8H, m), 2,82 (2H, c), of 4.54 (1H, users), 6,50 (1H, users), 6,93 (1H, users), 7,06-7,22 (3H, m), 7,26 (1H, users), 7,55 (1H, users), to 7.67 (1H, c), of 8.28 (1H, users), a 9.60 (1H, users).

mass: 445,447 (M+1)+

Example 12

Synthesis of TRANS-4-(3-chloro-2-pertenece)-N-methoxy-1-((6-(1,3-thiazol-2-ylamino)pyridine-2-yl)methyl)cyclohexanecarboxylic

Specified in the title compound was obtained as a pale yellow solid according to example 6, using the hydrochloride of O-methylhydroxylamine of mastogloia ammonium, which was used in example 6.

1H-NMR (CDCl3) δ: 1,80-of 2.15 (8H, m), of 3.07 (2H, c), of 3.64 (3H, c), to 4.46 (1H, users), 6,60 (1H, c), 6,70-7,03 (5H, m), 7,31 (1H, c), 7,47 (1H, t, J=7,6 Hz), 9,39 (1H, users).

mass: 491,493 (M+1)+

Example 13

Synthesis of 5-(TRANS-4-(2-fluoro-3-(trifluoromethyl)phenoxy)-1-((6-(1H-pyrazole-3-ylamino)pyridine-2-yl)methyl)cyclohexyl)-1,3,4-oxadiazol-2(3H)-it

(1) Synthesis of triptoreline TRANS-1-((6-((1-tert-butyl-1H-pyrazole-5-yl)amino)pyridin-2-yl)methyl)-4-(2-fluoro-3-(trifluoromethyl)phenoxy)cyclohexanecarboxylic acid

To a solution of 2.51 g of tert-butyl TRANS-1-((6-((1-tert-butyl-1H-pyrazole-5-yl)amino)pyridin-2-yl)methyl)-4-(2-fluoro-3-(trifluoromethyl)phenoxy)cyclohexanecarboxylate obtained at stage 7(5) of example 7, in 39 ml of chloroform at 0°C was added 19 ml triperoxonane acid, followed by stirring the reaction mixture at room temperature over night. The resulting solution was concentrated under vacuum, thus obtaining specified in the title compound as a yellow oil.

(2) Synthesis of tert-butyl 2-((TRANS-1-((6-((1-tert-butyl-1H-pyrazole-5-yl)amino)pyridin-2-yl)methyl)-4-(2-fluoro-3-(trifluoromethyl)phenoxy)cyclohexyl)carbonyl)hydrazinecarboxamide

To a solution of 3.2 g of triptoreline TRANS-1-((6-((1-tert-butyl-1H-pyrazole-5-yl)amino)pyridin-2-yl)methyl)-4-(2-fluoro-3-(thrift rmutil)phenoxy)cyclohexanecarboxylic acid 14.1 ml of chloroform at room temperature was sequentially added 5,62 g of tert-BUTYLCARBAMATE, of 3.27 g of the hydrate of 1-hydroxybenzotriazole and 4.13 g of the hydrochloride of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide, followed by stirring at room temperature for 8 hours. After adding to the reaction mixture ethyl acetate the organic layer was sequentially washed with water and saturated salt solution, dried over anhydrous magnesium sulfate, filtered and concentrated in vacuum. The obtained residue was purified by column chromatography on silica gel (eluent: hexane to a mixture of hexane/ethyl acetate = 1/4), while receiving specified in the title compound as a pale yellow solid.

(3) Synthesis of TRANS-1-((6-((1-tert-butyl-1H-pyrazole-5-yl)amino)pyridin-2-yl)methyl)-4-(2-fluoro-3-(trifluoromethyl)phenoxy)cyclohexanecarboxylate

To a solution of 2.93 g of tert-butyl 2-((TRANS-1-((6-((1-tert-butyl-1H-pyrazole-5-yl)amino)pyridin-2-yl)methyl)-4-(2-fluoro-3-(trifluoromethyl)phenoxy)cyclohexyl)carbonyl)hydrazinecarboxamide in 30 ml of chloroform at room temperature was added 15 ml triperoxonane acid, followed by stirring at room temperature for 1 hour. After concentrating the reaction mixture in vacuo the resulting residue was dissolved in chloroform. The chloroform solution is then washed with a saturated solution of sodium bicarbonate and a saturated solution with the Lee, was dried over anhydrous magnesium sulfate, filtered and concentrated in vacuum. The obtained residue was purified by column chromatography on silica gel (eluent: chloroform to the mixture chloroform/methanol = 10/1), while receiving specified in the title compound as a pale yellow solid.

(4) Synthesis of 5-(TRANS-1-((6-((1-tert-butyl-1H-pyrazole-5-yl)amino)pyridin-2-yl)methyl)-4-(2-fluoro-3-(trifluoromethyl)phenoxy)cyclohexyl)-1,3,4-oxadiazol-2(3H)-it

To a solution of 1.9 g of TRANS-1-((6-((1-tert-butyl-1H-pyrazole-5-yl)amino)pyridin-2-yl)methyl)-4-(2-fluoro-3-(trifluoromethyl)phenoxy)cyclohexanecarboxylate in 35 ml of tetrahydrofuran at room temperature was added 3,05 ml of N,N'-diisopropylethylamine and 1.70 g of 1,1'-carbonyldiimidazole. The reaction mixture was stirred at room temperature for 1.5 hours, followed by concentrating the resulting solution under vacuum. The obtained residue was purified by column chromatography on silica gel (eluent: chloroform to the mixture chloroform/methanol = 10/1), while receiving specified in the title compound as a pale yellow solid.

(5) Synthesis of 5-(TRANS-4-(2-fluoro-3-(trifluoromethyl)phenoxy)-1-((6-(1H-pyrazole-3-ylamino)pyridine-2-yl)methyl)cyclohexyl)-1,3,4-oxadiazol-2(3H)-it

The solution 2,11 g of 5-(TRANS-1-((6-((1-tert-butyln-pyrazole-5-yl)amino)pyridin-2-yl)methyl)-4-(2-fluoro-3-(trifluoromethyl)phenoxy)cyclohexyl)-1,3,4-oxadiazol-2(3H)-she's in 37 ml of formic acid was stirred at 95°C for 1.5 hours. After concentrating the reaction mixture in vacuo, the obtained residue was podslushivaet saturated sodium bicarbonate solution and was extracted with chloroform. The chloroform solution is then washed with water and saturated salt solution, dried over anhydrous magnesium sulfate, filtered and concentrated in vacuum. The obtained residue was purified by column chromatography on silica gel (eluent: chloroform to the mixture chloroform/methanol = 4/1), while receiving specified in the title compound as a white solid.

1H-NMR (CDCl3) δ: 1,63-of 1.80 (2H, m), 1,89-2,07 (6H, m), to 3.02 (2H, c), 4,47-a 4.53 (1H, m), 6,23 (1H, users), of 6.50 (1H, d, J=8.0 Hz), is 6.61 (1H, d, J=7,2 Hz), 7,06 (1H, users), 7,10-7,22 (3H, m), 7,35-7,42 (2H, m).

mass: 519 (M+1)+

Example 14

Synthesis of 5-(TRANS-4-(3-chloro-2-pertenece)-1-((6-(1H-pyrazole-3-ylamino)pyridine-2-yl)methyl)cyclohexyl)-1,3,4-oxadiazol-2(3H)-it

(1) Synthesis of TRANS-1-((6-((1-tert-butyl-1H-pyrazole-5-yl)amino)pyridin-2-yl)methyl)-4-(3-chloro-2-pertenece)cyclohexanecarbonitrile

Specified in the title compound was obtained as a pale yellow oil in the same way as in stage 7(4),(5) of example 7 and 13(1)-13(3) of example 13, using 3-chloro-2-terfenol instead of 2-fluoro-3-(trifluoromethyl)phenol, which was used in example 7(4).

(2) Synthesis of 5-(TRANS-4-(3-chloro-2-ftoh is noxy)-1-((6-(1H-pyrazole-3-ylamino)pyridine-2-yl)methyl)cyclohexyl)-1,3,4-oxadiazol-2(3H)-it

Specified in the title compound was obtained as white solid in the same manner as in the stages 13(4) and 13(5) of example 13, using TRANS-1-((6-((1-tert-butyl-1H-pyrazole-5-yl)amino)pyridin-2-yl)methyl)-4-(3-chloro-2-pertenece)cyclohexanecarboxylate instead of TRANS-1-((6-((1-tert-butyl-1H-pyrazole-5-yl)amino)pyridin-2-yl)methyl)-4-(2-fluoro-3-(trifluoromethyl)phenoxy)cyclohexanecarboxylate, which was used in example 13(4).

1H-NMR (DMSO-d6) δ: 1,65 is 2.00 (8H, m), of 2.97 (2H, c), 4,63 (1H, users), 6,30-of 6.45 (2H, m), 6,95-7,30 (4H, m), 7,46 (1H, t, J=8.0 Hz), of 7.48-7,56 (1H, m)to 9.15 (1H, c), 12,02 (1H, c), 12,07 (1H, users).

mass: 485,487 (M+1)+

Example 15

Synthesis of 5-(TRANS-4-(3-chloro-2-pertenece)-1-((6-(1H-pyrazole-3-ylamino)pyridine-2-yl)methyl)cyclohexyl)-1,3,4-oxadiazol-2(3H)-thione

(1) Synthesis of 5-(TRANS-1-((6-((1-tert-butyl-1H-pyrazole-5-yl)amino)pyridin-2-yl)methyl)-4-(3-chloro-2-pertenece)cyclohexyl)-1,3,4-oxadiazol-2(3H)-thione

To a solution of 97 mg of TRANS-1-((6-((1-tert-butyl-1H-pyrazole-5-yl)amino)pyridin-2-yl)methyl)-4-(3-chloro-2-pertenece)cyclohexanecarboxylate obtained at the stage of example 14(1), in 3 ml of ethanol at room temperature was added 0,078 ml of carbon disulfide and 0,432 ml of an ethanol solution containing 0,87M potassium hydroxide. The reaction mixture was stirred at 80°C for 3 hours, podci the Lyali 2M solution of hydrochloric acid and was extracted with ethyl acetate. An ethyl acetate solution was dried over anhydrous magnesium sulfate, filtered and concentrated in vacuum. The obtained residue was purified by column chromatography on silica gel (eluent: hexane to a mixture of hexane/ethyl acetate = 2/3), while receiving specified in the title compound as a pale yellow oil.

(2) Synthesis of 5-(TRANS-4-(3-chloro-2-pertenece)-1-((6-(1H-pyrazole-3-ylamino)pyridine-2-yl)methyl)cyclohexyl)-1,3,4-oxadiazol-2(3H)-thione

Specified in the title compound was obtained in the form of a solid pale yellow substance in the same way as in stage 13(5) of example 13, using 5-(TRANS-1-((6-((1-tert-butyl-1H-pyrazole-5-yl)amino)pyridin-2-yl)methyl)-4-(3-chloro-2-pertenece)cyclohexyl)-1,3,4-oxadiazol-2(3H)-tion instead of 5-(TRANS-1-((6-((1-tert-butyl-1H-pyrazole-5-yl)amino)pyridin-2-yl)methyl)-4-(2-fluoro-3-(trifluoromethyl)phenoxy)cyclohexyl)-1,3,4-oxadiazol-2(3H)-she, which was used in example 13(5).

1H-NMR (DMSO-d6) δ: 1,61-of 1.74 (2H, m), l,85-2,01 (6H, m), 2,96 (2H, c), 4,56 (1H, users), 6,24 (1H, c), 6,33 (1H, d, J=7,2 Hz), 6.90 to-7,00 (1H, m), 7,09-7,24 (3H, m), 7,37 (1H, t, J=7,6 Hz), of 7.48 (1H, c), 9,01 (1H, users).

mass: 501,503 (M+1)+

Example 16

Synthesis of 5-(TRANS-4-(3-chloro-2-pertenece)-1-((6-(1H-pyrazole-3-ylamino)pyridine-2-yl)methyl)cyclohexyl)-3-methyl-1,3,4-oxadiazol-2(3H)-it

Specified in the title compound was obtained in example 14 in which the IDA solid pale yellow substance, using tert-butyl 1-methylhydroperoxide instead of tert-BUTYLCARBAMATE, which was used in example 14.

1H-NMR (CDCl3) δ: 1,58-of 1.75 (2H, m), 1,96-2,05 (6N, m), 2,99 (2H, s), 3,20 (3H, s), 4,46 (1H, users), 6,09 (1H, s), 6,55 (1H, d, J=6.8 Hz), 6,77 (1H, d, J=8.0 Hz), 6,80-7,20 (4H, m), 7,42 (1H, t, J=7,6 Hz), 7,46 (1H, s).

mass: 499,501 (M+1)+

Example 17

Synthesis of 5-(TRANS-4-(3-chloro-2-pertenece)-1-((6-(1H-pyrazole-3-ylamino)pyrazin-2-yl)methyl)cyclohexyl)-1,3,4-oxadiazol-2(3H)-it

Specified in the title compound was obtained according to example 13 in the form of a white solid, using tert-butyl TRANS-1-((6-((1-tert-butyl-1H-pyrazole-5-yl)amino)pyrazin-2-yl)methyl)-4-(3-chloro-2-pertenece)cyclohexanecarboxylate, which is obtained at stage 10(8) of example 10.

1H-NMR (DMSO-d6) δ: 1.60-to of 1.95 (8H, m), of 2.92 (2H, c), of 4.57 (1H, users), 6,38 (1H, c), 7,10-of 7.25 (3H, m), 7,52 (1H, c), a 7.62 (1H, c), of 8.27 (1H, c), to 9.66 (1H, c), 11,98 (1H, c), 12,16 (1H, c).

mass: 486,488 (M+1)+

Example 18

Synthesis of triptoreline TRANS-4-((2,3-dichlorophenyl)thio)-1-((6-(1,3-thiazol-2-ylamino)pyridine-2-yl)methyl)cyclohexanecarboxylic acid

(1) Synthesis of tert-butyl TRANS-4-((2,3-dichlorophenyl)thio)-1-(((6-((2Z)-3-(methoxymethyl)-1,3-thiazol-2(3H)-ilidene)amino)pyridin-2-yl)methyl)cyclohexanecarboxylate

The solution to 107.4 mg of tert-butyl CIS-4-hydroxy-1-((6-(((2Z)-3-(methoxymethyl)-1,3-enous the l-2(3H)-ilidene)amino)pyridin-2-yl)methyl)cyclohexanecarboxylate, obtained in stage 1(6) of example 1, in 0,83 ml of tetrahydrofuran at 0°C was added 0,070 ml of triethylamine and 0,029 ml methanesulfonanilide, followed by stirring the reaction mixture at room temperature for 30 minutes. The precipitate was filtered and washed with tetrahydrofuran and the filtrate was concentrated in vacuum. The obtained residue was purified by column chromatography on silica gel (eluent: hexane to a mixture of hexane/ethyl acetate = 4/1), while receiving tert-butyl-CIS-1-((6-(((2Z)-3-(methoxymethyl)-1,3-thiazol-2(3H)-ilidene)amino)pyridin-2-yl)methyl)-4-((methylsulphonyl)oxy)cyclohexanecarboxylate.

To a solution of 110 mg of tert-butyl CIS-1-((6-(((2Z)-3-(methoxymethyl)-1,3-thiazol-2(3H)-ilidene)amino)pyridin-2-yl)methyl)-4-((methylsulphonyl)oxy)cyclohexanecarboxylate in 0.72 ml of N-methyl-2-pyrrolidinone at room temperature was added to 62.8 mg of potassium carbonate and 78,0 mg of 2,3-dichlorobenzoyl, followed by stirring the reaction mixture at 80°C during the night. The reaction mixture was cooled to room temperature, was added to the reaction mixture water and was extracted with ethyl acetate. An ethyl acetate layer was washed with saturated salt solution, dried over anhydrous magnesium sulfate, filtered and concentrated in vacuum. The obtained residue was purified by column chromatography on silica gel (eluent: hexane to hexane mixture/acilac is tat = 1/4), while receiving specified in the title compound as a yellow oil.

(2) Synthesis of triptoreline TRANS-4-((2,3-dichlorophenyl)thio)-1-((6-(1,3-thiazol-2-ylamino)pyridine-2-yl)methyl)cyclohexanecarboxylic acid

To 39,0 mg of tert-butyl TRANS-4-((2,3-dichlorophenyl)thio)-1-((6-(((2Z)-3-(methoxymethyl)-1,3-thiazol-2(3H)-ilidene)amino)pyridin-2-yl)methyl)cyclohexanecarboxylate was added 1 ml of a 4M solution of hydrogen chloride in 1,4-dioxane, followed by stirring the reaction mixture at 95°C for 2.5 hours. After cooling the reaction mixture to room temperature the reaction mixture was concentrated in vacuum. The obtained residue was purified using preparative liquid chromatography with reversed phase with the subsequent concentration of the fractions obtained in vacuum, thus obtaining specified in the title compound as a white solid.

1H-NMR (DMSO-d6) δ: 1,71 is 1.96 (8H, m)of 3.00 (2H, c), of 3.64 (1H, users), 6,74 (1H, d, J=7,6 Hz)6,91 (1H, d, J=8.0 Hz), 7,03 (1H, d, J=4.0 Hz), 7,31 (1H, t, J=8.0 Hz), 7,40 (1H, d, J=4.0 Hz), 7,41-7,47 (2H, m), 7,60 (1H, DD, J=8,0, a 7.6 Hz), 11,40 (1H, users).

mass: 494,496 (M+1)+

Example 19

Synthesis of triptoreline TRANS-4-((2,3-dichlorophenyl)sulfinil)-1-((6-(1,3-thiazol-2-ylamino)pyridine-2-yl)methyl)cyclohexanecarboxylic acid

To a suspension of 8.0 mg trifenatate TRANS-4-((2,3-dichloro enyl)thio)-1-((6-(1,3-thiazol-2-ylamino)pyridine-2-yl)methyl)cyclohexanecarboxylic acid, obtained according to example 18, of 0.24 ml of acetonitrile and 0.12 ml of water at room temperature was added a solution of 8.6 mg drug OXONE®(peroxymonosulfate potassium provided by the company Aldrich) of 0.12 ml of water, followed by stirring the reaction mixture at room temperature for 2 hours. The reaction mixture was concentrated in vacuum. The obtained residue was purified using preparative liquid chromatography with reversed phase with the subsequent concentration of the fractions obtained in vacuum, thus obtaining specified in the title compound as a white solid.

1H-NMR (CD3OD) δ: 1,26-of 1.41 (1H, m), 1,73-to 1.82 (1H, m), 1.85 to of 2.21 (6H, m), 3,05 is 3.15 (1H, m), 3,29 (2H, s), 7,07 (1H, d, J=8.0 Hz), 7,11 (1H, d, J=7,6 Hz), 7,28 (1H, d, J=4.0 Hz), to 7.59 (1H, d, J=4.0 Hz), to 7.59 (1H, t, J=8.0 Hz), 7,71 for 7.78 (2H, m), 7,83 (1H, t, J=8.0 Hz).

mass: 510,512 (M+1)+

Example 20

Synthesis of triptoreline TRANS-4-((2,3-dichlorophenyl)sulfonyl)-1-((6-(1,3-thiazol-2-ylamino)pyridine-2-yl)methyl)cyclohexanecarboxylic acid

To a suspension 6,60 mg trifenatate TRANS-4-((2,3-dichlorophenyl)thio)-1-((6-(1,3-thiazol-2-ylamino)pyridine-2-yl)methyl)cyclohexanecarboxylic acid obtained in example 18, in 0.24 ml of acetonitrile and 0.12 ml of water at room temperature was added a solution of 14.7 mg drug OXONE®(peroxymonosulfate potassium) of 0.12 ml of water followed by paramesh the cation of the reaction mixture at room temperature over night. The reaction mixture was concentrated in vacuum. The obtained residue was purified using preparative liquid chromatography with reversed phase with the subsequent concentration of the fractions obtained in vacuum, thus obtaining specified in the title compound as a white solid.

1H-NMR (DMSO-d6) δ: 1,59 to 1.76 (4H, m), 1.85 to of 1.92 (2H, m), 1,98-2,11 (2H, m), to 3.02 (2H, c), 3,61-3,70 (1H, m), of 6.65 (1H, d, J=8.0 Hz), 6,86 (1H, d, J=8.0 Hz), 7,01 (1H, J=3.6 Hz), 7,38 (1H, d, J=3.6 Hz), 7,56 (1H, t, J=8.0 Hz), the 7.65 (1H, t, J=8.0 Hz), 8,03 (2H, d, J=8.0 Hz), of 11.15 (1H, users).

mass: 526,528 (M+1)+

Example 21

Synthesis of triptoreline TRANS-4-((2,3-dichlorophenyl)thio)-1-((6-(1H-pyrazole-3-ylamino)pyridine-2-yl)methyl)cyclohexanecarboxylic acid

(1) Synthesis of tert-butyl CIS-1-((6-((1-tert-butyl-1H-pyrazole-5-yl)amino)pyridin-2-yl)methyl)-4-hydroxycyclohexanecarboxylate

Specified in the title compound was obtained as yellow solid substance in the same way as in stage 7(5) of example 7 using tert-butyl CIS-1-((6-bromopyridin-2-yl)methyl)-4-hydroxycyclohexanecarboxylate obtained at stage 7(3) of example 7, instead of tert-butyl TRANS-1-((6-bromopyridin-2-yl)methyl)-4-(2-fluoro-3-(trifluoromethyl)phenoxy)cyclohexanecarboxylate, which was used in example 7(5).

(2) Synthesis of tert-butyl TRANS-1-((6-((1-tert-butyl-1H-pyrazole-5-yl)amino)pyridine-2-the l)methyl)-4-((2,3-dichlorophenyl)thio)cyclohexanecarboxylate

Specified in the title compound was obtained in the form of not quite white solid in the same way as in stage 18(1) of example 18, using tert-butyl CIS-1-((6-((1-tert-butyl-1H-pyrazole-5-yl)amino)pyridin-2-yl)methyl)-4-hydroxycyclohexanecarboxylate instead of tert-butyl CIS-4-hydroxy - 1-((6-(((2Z)-3-(methoxymethyl)-1,3-thiazole-2(3H)-ilidene)amino)pyridin-2-yl)methyl)cyclohexanecarboxylate, which were used at stage 18(1) of example 18.

(3) Synthesis of triptoreline TRANS-4-((2,3-dichlorophenyl)thio)-1-((6-(1H-pyrazole-3-ylamino)pyridine-2-yl)methyl)cyclohexanecarboxylic acid

Specified in the title compound was obtained as white solid in the same way as in stage 7(6) of example 7 using tert-butyl TRANS-1-((6-((1-tert-butyl-1H-pyrazole-5-yl)amino)pyridin-2-yl)methyl)-4-((2,3-dichlorophenyl)thio)cyclohexanecarboxylate instead of tert-butyl TRANS-1 -((6-((1-tert-butyl-1H-pyrazole-5-yl)amino)pyridin-2-yl)methyl)-4-(2-fluoro-3-(trifluoromethyl)phenoxy)cyclohexanecarboxylate, which was used to stage 7(6) of example 7.

1H-NMR (CD3OD) δ: 1.77 in-2,12 (8H, m), up 3.22 (2H, c), 3,60-3,70 (1H, m), 6,13 (1H, d, J=2.4 Hz), of 6.99 (1H, d, J=8.0 Hz), 7,14 (1H, d, J=8.0 Hz), 7,24 (1H, t, J=8.0 Hz), 7,37 (1H, DD, J=8,0, 1.2 Hz), 7,40 (1H, DD, J=7,6, 1.2 Hz), of 7.75 (1H, d, J=2.4 Hz), 8,01 (1H, DD, J=8.0 a, 7,6 Hz).

mass: 477,479 (M+1)+

Example 22

Synthesis of triptoreline 5-(Tran is-4-((2,3-dichlorophenyl)thio)-1-((6-(1H-pyrazole-3-ylamino)pyridine-2-yl)methyl)cyclohexyl)-1,3,4-oxadiazol-2(3H)-it

Specified in the title compound was obtained as white solid in the same manner as in the stages 13(2)-13(4) of example 13, using triptorelin TRANS-4-((2,3-dichlorophenyl)thio)-1-((6-(1H-pyrazole-3-ylamino)pyridine-2-yl)methyl)cyclohexanecarboxylic acid, obtained in example 21 instead of triptoreline TRANS-1-((6-((1-tert-butyl-1H-pyrazole-5-yl)amino)pyridine-2-yl)methyl)-4-(2-fluoro-3-(trifluoromethyl)phenoxy)cyclohexanecarboxylic acid, which was used in example 13(2).

1H-NMR (CD3OD) δ: 1,82-of 1.92 (2H, m), 1,96-2,17 (6H, m), 3,29 (2H, c), 3,66-and 3.72 (1H, m), 6,14 (1H, d, J=2,8 Hz), of 6.99 (1H, d, J=7,6 Hz), 7,17 (1H, d, J=8,8 Hz), 7,25 (1H, t, J=8.0 Hz), 7,38 (1H, DD, J=8.0 a, and 1.6 Hz), 7,41 (1H, DD, J=8.0 a, 1,6 Hz), of 7.75 (1H, d, J=2,8 Hz), 8,02 (1H, DD, J=8,8, 7,6 Hz).

mass: 517,519 (M+1)+

Example 23

Synthesis of triptoreline 5-(TRANS-4-((2,3-dichlorophenyl)sulfinil)-1-((6-(1H-pyrazole-3-ylamino)pyridine-2-yl)methyl)cyclohexyl)-1,3,4-oxadiazol-2(3H)-it

Specified in the title compound was obtained in example 19 in the form of a white solid, using triptorelin 5-(TRANS-4-((2,3-dichlorophenyl)thio)-1-((6-(1H-pyrazole-3-ylamino)pyridine-2-yl)methyl)cyclohexyl)-1,3,4-oxadiazol-2(3H)-she obtained in example 22, instead of triptoreline TRANS-4-((2,3-dichlorophenyl)thio)-1-((6-(1,3-thiazol-2-ylamino)pyridine-2-yl)methyl)cyclohexanecarboxylic acid, which was used in Primera.

1H-NMR (CD3OD) δ: 1,45-of 1.56 (1H, m), 1,86 of 1.99 (1H, m), 2.00 in of 2.23 (6H, m), 3,12 is 3.23 (1H, m)to 3.36 (1H, d, J=14.4 Hz), 3,42 (1H, d, J=14.4 Hz), x 6.15 (1H, d, J=2,8 Hz), 6,97 (1H, d, J=7,2 Hz), 7,17 (1H, d, J=8,8 Hz), a 7.62 (1H, DD, J=8.0 a, 7,2 Hz), 7,76-7,80 (3H, m), 8,03 (1H, DD, J=8,8, 7,2 Hz).

mass: 533,535 (M+1)+

Example 24

Synthesis of triptoreline 5-(TRANS-4-((2,3-dichlorophenyl)sulfonyl)-1-((6-(1H-pyrazole-3-ylamino)pyridine-2-yl)methyl)cyclohexyl)-1,3,4-oxadiazol-2(3H)-it

Specified in the title compound was obtained in example 20 in the form of hard yellow substance, applying triptorelin 5-(TRANS-4-((2,3-dichlorophenyl)thio)-1-((6-(1H-pyrazole-3-ylamino)pyridine-2-yl)methyl)cyclohexyl)-1,3,4-oxadiazol-2(3H)-she obtained in example 22, instead of triptoreline TRANS-4-((2,3-dichlorophenyl)thio)-1-((6-(1,3-thiazol-2-ylamino)pyridine-2-yl)methyl)cyclohexanecarboxylic acid, which was used in example 20.

1H-NMR (CD3OD) δ: 1,90-of 2.25 (8H, m)to 3.34 (2H, c), of 3.73-a 3.83 (1H, m), x 6.15 (1H, d, J=2,8 Hz), 6,97 (1H, d, J=7,2 Hz), 7,17 (1H, d, J=8,8 Hz), 7,58 (1H, t, J=8.0 Hz), to 7.77 (1H, d, J=2,8 Hz), to 7.93 (1H, DD, J=8.0 a, 1,6 Hz), 8,02 (1H, DD, J=8,8, 7,2 Hz), of 8.09 (1H, DD, J=8.0 a, 1,6 Hz).

mass: 549,551 (M+1)

Link 1

Synthesis of tert-butyl 4-((tert-butyl(diphenyl)silyl)oxy)cyclohexanecarboxylate

(1) Synthesis of ethyl-4-((tert-butyl(diphenyl)silyl)oxy)cyclohexanecarboxylate

To a solution of 25 g of 4-hydroxycyclohexyl Borovoy acid in 125 ml of N,N-dimethylformamide under ice cooling sequentially added to 21.7 g of imidazole and 39.6 ml of tert-butyl(diphenyl)silingardi, followed by stirring the reaction mixture at room temperature within 3 hours. To the reaction mixture was added water and was extracted with hexane. The obtained hexane solution was washed with saturated salt solution, dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated under vacuum, thus obtaining specified in the header of the connection.

(2) Synthesis of 4-((tert-butyl(diphenyl)silyl)oxy)cyclohexanecarboxylic acid

To a solution 64,2 g ethyl-4-((tert-butyl(diphenyl)silyl)oxy)cyclohexanecarboxylate in 200 ml of methanol and 200 ml of tetrahydrofuran was added 58 ml of 5M aqueous sodium hydroxide solution, followed by stirring at room temperature over night. The reaction mixture was neutralized 5M aqueous solution of hydrochloric acid (hydrochloride) with subsequent removal of methanol and tetrahydrofuran in vacuo and the resulting residue was extracted with ethyl acetate. Received an ethyl acetate solution was washed with saturated salt solution, dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated under vacuum, thus obtaining specified in the header of the connection.

(3) Synthesis of tert-butyl 4-((tert-butyl(diphenyl)silyl)oxy)cyclohexanecarboxylate

To a solution of 62.8 g of 4-((tert-butyl(diphenyl)silyl)oxy)cyclohexanecarboxylic acid in 270 ml of tert-butyl alcohol at room is based temperature was sequentially added and 63.3 g of di-tert-BUTYLCARBAMATE and 5.31g 4-dimethylaminopyridine, followed by stirring the reaction mixture at room temperature for 3 hours. Removal of the tert-butyl alcohol, the reaction mixture was concentrated in vacuo and the resulting residue was purified by column chromatography on silica gel (eluent: hexane to a mixture of hexane/ethyl acetate = 19/1), while receiving specified in the title compound as a pale yellow oil.

Link 2

Synthesis of 4-((tert-butyl(diphenyl)silyl)oxy)cyclohexanecarbonitrile

(1) Synthesis of 4-((tert-butyl(diphenyl)silyl)oxy)cyclohexanecarboxylate

To a solution 6,64 g of 4-((tert-butyl(diphenyl)silyl)oxy)cyclohexanecarboxylic acid, obtained in stage 1(2) references 1, in 100 ml of chloroform at room temperature was sequentially added with 4.65 g of ammonium chloride, 30,3 ml diisopropylethylamine, 8.0 g of hydroxybenzotriazole hydrate and 10.0 g of the hydrochloride of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide, followed by stirring the reaction mixture at room temperature over night. The reaction mixture was washed with water and saturated salt solution, dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated in vacuum. The obtained residue was purified by column chromatography on silica gel (eluent: hexane/ethyl acetate = 10/1 to ethyl acetate), thus obtaining specified in the header of the connection.

2) Synthesis of 4-((tert-butyl(diphenyl)forces the l)oxy)cyclohexanecarbonitrile

To a solution of 6.42 per g of 4-((tert-butyl(diphenyl)silyl)oxy)cyclohexanecarboxylate and 2,39 ml of dimethyl sulfoxide in 90 ml of methylene chloride at -78°C was added a solution of 2.06 ml oxalicacid in 10 ml of methylene chloride, followed by stirring the reaction mixture at -78°C for 15 minutes. To the reaction mixture at -78°C was added 7,05 ml of triethylamine, followed by stirring the reaction mixture at -78°C for 30 minutes and further stirring for 1.5 hours at room temperature. The reaction mixture was washed with water and saturated salt solution, dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated in vacuum. The obtained residue was purified by column chromatography on silica gel (eluent: hexane to a mixture of hexane/ethyl acetate = 4/1), while receiving specified in the title compound as a pale yellow oil.

Link 3

Synthesis of 1-tert-butyl-1H-pyrazole-5-amine

To 600 ml of ethanol at room temperature was sequentially added 59,94 g of the hydrochloride tert-butylhydrazine, to 79.3 g of sodium acetate and 50 ml of 2-chloroacrylonitrile, followed by stirring the reaction mixture at 80°C for 12 hours. After removal of the solvent in vacuo the residue was added water. The mixture was neutralized with sodium bicarbonate which was extracted with ethyl acetate. Received an ethyl acetate solution was washed with saturated salt solution, dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated in vacuum. The obtained residue was purified by column chromatography on silica gel (eluent: hexane/ethyl acetate = 2/1-1/2), while receiving specified in the title compound as a pale yellow oil.

Link 4

Synthesis of 1-tert-butyl-1H-pyrazole-5-amine-n-toluensulfonate

To 850 ml of ethanol at room temperature was sequentially added 85,64 g of the hydrochloride tert-butylhydrazine, 112,54 g of sodium acetate and 72 ml of 2-chloroacrylonitrile, followed by stirring the reaction mixture at 80°C for 12 hours. After removal of the solvent in vacuo the residue was added water. The mixture was neutralized with sodium bicarbonate and was extracted with ethyl acetate. Received an ethyl acetate solution was washed with saturated salt solution, dried over anhydrous magnesium sulfate, filtered and the filtrate concentrated in vacuum. To a solution of the obtained residue in 700 ml of ethyl acetate under stirring solution was added 96,16 g of the hydrate p-toluensulfonate acid in 140 ml of ethanol, followed by leaving the mixture as it is at night. The precipitate was collected and washed with ethyl acetate, thus obtaining specified in the header with the Association in the form of a white solid.

Industrial applicability

The connection according to the invention is characterized in that it has inhibitory activity against the growth of cells, as well as a synergistic effect when used with other anticancer means, based on an excellent selective inhibitory activity against Aurora A, and because of this it is expected that it applies as antitumor agents in pharmaceuticals.

1. The compound of General formula I:

where R1represents COORa1, CONRa2Ra2', CONRa4ORa4',
where each of Ra1and Ra4represents a hydrogen atom;
each of Ra2andRa2'represents a hydrogen atom;
Ra4'represents lower alkyl; or
R1represents a heterocyclic group selected from the following groups, where Y2represents a hydrogen atom or lower alkyl:

R2represents O, S, SO, SO2;
R3represents phenyl, which is substituted by 2 substituents selected from halogen, CF3;
X2represents CH or N;
W represents the following balance:

where W1is the or S;
W2represents CH;
W3represents C or N; and,
at least one of W1, W2and W3represents a carbon atom; or its pharmaceutically acceptable salt or ester.

2. The compound according to claim 1 or its pharmaceutically acceptable salt or ester, where W is selected from:
,
where W2arepresents hydrogen.

3. The compound according to claim 2 or pharmaceutically acceptable salt or ester, where R3represents phenyl, 2-nd and 3-th position of which is substituted with two substituents selected from F, Cl and CF3.

4. The compound according to claim 3 or its pharmaceutically acceptable salt or ester where X2represents CH.

5. The compound according to claim 4 or pharmaceutically acceptable salt or ester, where R1represents COOH or CONRa2Ra2'where Ra2and Ra2'each represents a hydrogen atom; or R1selected from the following:
,,
and R2represents O, S, SO or SO2.

6. The compound according to claim 5 or its pharmaceutically acceptable salt or ester, where W is any of the following residues:
,

7. The connection which is:
(a) TRANS-4-(3-chloro-2-pertenece)-1-((6-(1,3-thiazol-2-ylamino)pyridine-2-yl)methyl)cyclohexanecarbonyl acid;
(b) TRANS-4-(2-fluoro-3-(trifluoromethyl)phenoxy)-1-((6-(1,3-thiazol-2-ylamino)pyridine-2-yl)methyl)cyclohexanecarbonyl acid;
(c) TRANS-4-(2,3-dichlorophenoxy)-1-((6-(1,3-thiazol-2-ylamino)pyridine-2-yl)methyl)cyclohexanecarbonyl acid;
(d) TRANS-4-(2-fluoro-3-(trifluoromethyl)phenoxy)-1-((6-(1H-pyrazole-3-ylamino)pyridine-2-yl)methyl)cyclohexanecarbonyl acid;
(e) TRANS-4-(3-chloro-2-pertenece)-1-((6-(1H-pyrazole-3-ylamino)pyrazin-2-yl)methyl)cyclohexanecarboxylic;
(f) 5-(TRANS-4-(2-fluoro-3-(trifluoromethyl)phenoxy)-1-((6-(1H-pyrazole-3-ylamino)pyridine-2-yl)methyl)cyclohexyl)-1,3,4-oxadiazol-2(3H)-he;
(g) 5-(TRANS-4-(3-chloro-2-pertenece)-1-((6-(1H-pyrazole-3-ylamino)pyridine-2-yl)methyl)cyclohexyl)-1,3,4-oxadiazol-2(3H)-he;
(h) 5-(TRANS-4-(3-chloro-2-pertenece)-1-((6-(1H-pyrazole-3-ylamino)pyrazin-2-yl)methyl)cyclohexyl)-1,3,4-oxadiazol-2(3H)-he, or
(i) 5-(TRANS-4-((2,3-dichlorophenyl)sulfonyl)-1-((6-(1H-pyrazole-3-ylamino)pyridine-2-yl)methyl)cyclohexyl)-1,3,4-oxadiazol-2(3H)-he,
or its pharmaceutically acceptable salt or ester.

8. The Union, representing

TRANS-4-(3-chloro-2-pertenece)-1-((6-(1,3-thiazol-2-ylamino)pyridine-2-yl)methyl)cyclohexanecarbonyl acid,
or its pharmaceutically acceptable salt or ester.

9. Connected to the e, representing

5-(TRANS-4-(3-chloro-2-pertenece)-1-((6-(1H-pyrazole-3-ylamino)pyridine-2-yl)methyl)cyclohexyl)-1,3,4-oxadiazol-2(3H)-he,
or its pharmaceutically acceptable salt or ester.

10. Pharmaceutical composition having a selective inhibitory activity against Aurora A, containing, together with a pharmaceutically acceptable carrier or diluent, at least one compound according to claim 1 as an active ingredient.

11. Selective inhibitor of Aurora A, containing, together with a pharmaceutically acceptable carrier or diluent, at least one compound according to claim 1 as an active ingredient.



 

Same patents:

FIELD: chemistry.

SUBSTANCE: invention relates to novel organic compounds of formula where R1 denotes H; halogen; -C0-C7-alkyl-O-R3; -NR4R5; R2 denotes phenyl, substituted with one or two substitutes selected from a group consisting of C1-7alkyl, halogen-C1-7alkyl, C1-7alkoxy, halogen-C1-7alkoxy, phenoxy, halogen, C1-7alkylpiperazinyl-C1-7alkyl, C3-C8-cyclalkyl, C1-7alkylpiperidinyl-C1-7alkyl and C1-7alkylimidazolyl; R3 denotes H or phenyl-lower alkyl; R4 and R5 are independently selected from a group consisting of H; lower alkyl; lower alkoxy-carbonyl and amino; A, B and X are independently selected from C(R7) or N, provided that not more than one or A, B and X denotes N; R7 denotes H; R8 denotes hydrogen; n equals 0; Y denotes O; Z denotes C; W is absent; K denotes N or C, and either a) if K denotes C, the bond shown by a wavy line () is a double bond, Q is selected from O-N, S-N, O-CH and S-CH, where in each case, the left-hand O or S atom is bonded through a bond shown in formula I to K, the right-hand N or carbon (CH) atom is bonded to C through a bond shown by a dotted line () in formula I, provided that said bond, which is shown by the dotted line, is a double bond with C; and the bond shown by a thick line () is a single bond; or b) if K denotes N, the bond shown by a wavy line () is a single bond; Q denotes N=CH, where the left-hand N atom is bonded through a bond shown in formula I to K, the right-hand carbon (CH) atom is bonded to C through a bond shown by a dotted line () in formula I, provided that said bond, which is shown by a dotted line, is a single bond with C; and the bond shown by thick line () is a double bond; or salt thereof (preferably pharmaceutically acceptable salt). The invention also relates to a pharmaceutical composition, having inhibiting action on protein kinase, containing a compound of formula I or salt thereof in an effective amount and at least one pharmaceutically acceptable carrier material.

EFFECT: heterocyclic carboxamides as kinase inhibitors.

12 cl, 25 ex

FIELD: chemistry.

SUBSTANCE: present invention relates to a compound of formula I or a pharmaceutically acceptable salt thereof, where R1 denotes C1-C8-alkylaminocarbonyl, which is optionally substituted with a 5- or 6-member heterocyclic ring containing 3-4 ring heteroatoms selected from a group consisting of oxygen, nitrogen and sulphur, where the ring can be optionally substituted with C1-C8-alkyl or C1-C8-alkoxy group ; R2 denotes C1-C3-alkyl or a halogen; one of R3 and R4 denotes R6, and the other denotes R7; R5 denotes hydrogen or halogen; R6 denotes hydrogen, hydroxy group amino group, -SO2R8, -SO2NH2, -SO2NR9R10, -COR8, -CONHR8, -NHSO2R8, nitrile, carboxy, -OR8 or C1-C8-halogenalkyl; R7 denotes hydrogen, OR11, halogen, carboxy, -SO2R8, cyanogroup or C1-C8-halogenalkyl, or when R4 denotes R7, then R7 can also denote -NR12 R13 ; R8 R11 independently denote C1-C8-alkyl or C3-C8-cycloalkyl, which can be optionally substituted with hydroxy group, C1-C8-alkoxy group, nitrile, amino group, C1-C8-alkylamino group or di-C1-C8-alkyl)amino group; any R9 denotes C1-C8-alkyl or C3-C8-cycloalkyl, which can optionally be substituted with hydroxy group, C1-C8-alkoxy group, nitrile, amino group, C1-C8-alkylamino group, di(C1-C8-alkyl)amino group or a 5- or 6-member heterocyclic ring containing one or two ring heteroatoms selected from a group consisting of oxygen and nitrogen, where the ring can optionally be substituted with C1-C8-alkyl, and R10 denotes hydrogen or C1-C8-alkyl; or R9 and R10 together with a nitrogen atom with which they are bonded form a 5- or 6-member heterocyclic ring which can contain one or two additional nitrogen heteroatoms, where the ring can be optionally substituted with C1-C8-alkyl; any R12 denotes C1-C8-alkyl or C3-C8-cycloalkyl which can be optionally substituted with di(C1-C8-alkyl)aminogroup, and R13 denotes hydrogen or C1-C8-alkyl; or R12 and R13 together with a nitrogen atom with which they are bonded form a 5- or 6-member heterocyclic ring which contains one or two additional nitrogen heteroatoms, where the ring can optionally be substituted with C1-C8-alkyl.

EFFECT: possibility of using the compounds to produce a pharmaceutical agent for treating diseases mediated by phosphatidylinositol-3 kinase.

6 cl, 3 tbl, 181 ex

FIELD: chemistry.

SUBSTANCE: invention relates to hydroximoyl-tetrazole derivatives of formula (I), , where T is a tetrazole substitute, A is a phenyl or heterocycle, L1 and L2 are different linker groups, and Q is a carbocycle, use thereof as fungicide active agents, particularly in form of fungicide compositions, and methods of controlling phytopathogenic fungi, especially plants, using said compounds or compositions.

EFFECT: more effective use of the compounds.

13 cl, 2 tbl, 2 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel diarylamine-containing compounds of formula (I) or formula (4b), pharmaceutically acceptable salts thereof, which have c-kit inhibiting properties. In formulae (I) and (4b), each R1 independently denotes H, -C(O)OH and -L1-C1-6alkyl, where L1 denotes -O- or -C(O)O-, or any two neighbouring R1 groups can together form a 5-6-member heterocyclic ring containing a nitrogen atom or an oxygen atom as a heteroatom, a 6-member heterocyclic ring with one or two nitrogen atom s as heteroatoms, optionally substituted with a C1-4alkyl, and R5 denotes hydrogen or C1-C6alkyl; values of radicals Ar and Q are given in the claim. The invention also relates to a pharmaceutical composition containing said compounds, and a method of treating diseases whose development is promoted by c-kit receptor activity.

EFFECT: more effective use of the compounds.

17 cl, 3 tbl, 9 ex

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of general formula where R denotes a thiazolyl group of formula R2 and R3 are selected from: hydrogen, C1-C3linear alkyl; R4 is selected from: C1-C3linear or C3cyclic alkyl, phenyl and thiophenyl; Z denotes a group of formula: -(L)n-R1; R1 is selected from: i) C1-C3linear or branched alkyl, optionally substituted with C1-C4alkoxycarbonyl, halogen; ii) substituted phenyl or substituted with one or two substitutes selected from halogen, methoxy- or hydroxy group, C1-C4alkoxycarbonyl; iii) dioxopiperazinyl and 2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl, substituted with C1-C3alkyl; or iv) heteroaryl rings containing 5-10 atoms selected from thiazole, triazole, 1H-imidazole, thiadiazole, oxazole, isoxazole, oxadiazole, benzodioxole, benzo(1,4)dioxepanyl, pyridine, pyrimidine, 1H-indole, 2,3-dihydrobenzo[b][1,4]dioxynil, which can be substituted with oine or two substitutes selected from: a) hydroxy; b) C1-C3alkyl (which can be substituted with one more two substitutes selected from: ) phenyl; ii) C1-C4alkoxycarbonyl; iii) naphthalenyl; iv) 2-methylthiazolyl) ; c) NHC(O)C1-C3alkyl; d) C1-C4alkoxycarbonyl; e) 1 -(tert-butoxycarbonyl)-2-phenylethyl; f) methoxybenzyl; g) phenyl which can be substuted with C1-C4alkoxy, halogen, methoxycarbonyl or >NHC(O)CH3; h) (methoxy-2-oxoethyl)carbamoyl; L denotes a group selected from: i) C(O)NH[C(R5aR5b)]w-; ii) -C(O)[C(R6aR6b)]x-; iii) -C(O)[C(R7aR7b)]yC(O)-; iv) -SO2[C(R8aR8b)]z-; R5a, R5b, R6a, R6b, R7a, R7b, R8a and R8b, each independently denotes: i) hydrogen; ii) C1-C3 linear alkyl which can be substituted with 1 or 2 halogen atoms; iii) phenyl which can be substituted with 1-2 substitutes selected from halogen and lower alkoxy; iv) heteroaryl rings selected from imidazolyl, imidazolyl substituted with methyl, benzo(1,4)oxazinyl, oxadiazolyl substituted with methyl; index n equals 0 or 1; indices w, x, y and z are each independently equal to a number from 1 to 3. The invention also relates to pharmaceutically acceptable salts of compounds of formula (I) and use of compounds of formula (I) to prepare a medicinal agent for treating protein tyrosine phosphatase beta-mediated conditions.

EFFECT: obtaining compounds of formula (I) as human protein tyrosine phosphatase beta (HPTP-β) inhibitors.

15 cl, 17 dwg, 13 tbl, 16 ex

FIELD: chemistry.

SUBSTANCE: invention relates to an isoxazoline-substituted benzamide derivative of formula or salt thereof, where A1 denotes a carbon or nitrogen atom, A2 and A3 independently denote a carbon atom, G denotes a benzene ring, W denotes an oxygen or sulphur atom, X denotes a halogen atom or C1-C6alkyl, arbitrarily substituted with a radical R4, Y denotes a halogen atom, cyano, nitro, C1-C6alkyl, C1-C6alkyl arbitrarily substituted with radical R4, -OR5, -N(R7)R6, phenyl, D-41, when n equals 2, each Y can be identical or different from each other, R1 denotes -C(R1b)=NOR1a, M-5, -C(O)OR1c, -C(O)SR1c, -C(S)OR1c, -C(S)SR1c, -C(O)N(R1e)R1d, -C(S)N(R1e)R1d, -C(R1d)=NN(R1e)R1lf, phenyl, phehnyl substituted with (Z)p1, or D-3, D-8, D-13-D-15, D-21, D-35, D-52-D-55 or D-57-D-59, R2 denotes C1-C6alkyl, -CH2R14a, E-5, C3-C6alkynyl, -C(O)R15, -C(O)OR15, -C(O)C(O)OR15 or -SR15, where, when R1 denotes -C(R1b)=NOR1a, M-5, or -C(R1b)=NN(R1e)R1f, R2 can denote a hydrogen atom, when R1 denotes -C(O)OR1c, -C(O)SR1c, -C(S)OR1c or -C(S)SR1c, R2 can denote hydrogen, when R denotes -C(O)N(R1e)R1d or -C(S)N(R1c)R1d, R2 can denote a hydrogen atom, when R1 denotes phenyl, phenyl substituted with (Z)p1, or D-3, D-8, -D-13-D-15, D-21, D-35, D-52-D-55 or D-57-D-59 R2 can denote C1-C6halogenalkyl, C1-C6alkyl arbitrarily substituted with a radical R14a, C3-C6alkenyl, -C(O)NH2, -C(O)N(R16)R15, or R2 together with R1 can form =C(R2b)R2a, R3 denotes C1-C6alkyl arbitrarily substituted with radical R4, D-1, D-3, D-8, D-13-D-15, D-21, D-35, D-41, D-52-D-55, D-57-D-59 denote aromatic heterocyclic rings, m equals an integer from 2 to 3, n equals an integer from 0 to 2.

EFFECT: isoxazoline-substituted benzamide derivative and salt thereof are used in pest control, against harmful arthropods in agriculture and horticulture or in livestock farming and in the field of hygiene.

12 cl, 18 tbl, 73 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a method of producing 1,7-bis[4(5)-methyl-1,3-thiazol-2-yl]-3,5-dithia-1,7-diazaheptanes of general formula (1), which can be used in organic synthesis to produce macro-heterocyclic rings, as well as sorbents and extraction agents for precious and rare-earth metals. The method is realised by reacting hydrogen sulphide-saturated aqueous formaldehyde solution (37%) with 2-amino-4(5)-methylthiazole with molar ratio of initial reagents 2-amino-4(5)-methylthiazole: formaldehyde: hydrogen sulphide equal to 20:30:20, at temperature -5-5°C and atmospheric pressure for 8-12 hours.

EFFECT: improved method.

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of general formula

, where R is a group selected from: i) hydrogen; ii) phenyl and iii) thiophenyl; Z is a substituted or unsubstituted [1,3,4]thiadiazol-2-yl group, R1 is selected from: i) hydrogen; ii) straight C1-C6alkyl; iii) C6 or C10 aryl; iv) C(O)OR5; and v) 2-methylthiazol-4-yl; R5 denotes a straight or branched C1-C6alkyl; and index x equals 0 or 1. The invention also relates to use of compounds of formula (I) to prepare a medicinal agent having human protein tyrosine phosphatase beta (HPTP-β) inhibiting action and use in treatment.

EFFECT: compounds can be used as human protein tyrosine phosphatase beta inhibitors.

11 cl, 1 dwg, 1 tbl, 1 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a use of N-(2-thiazolyl)amide derivatives of formula

,

where R1 and R2 are independently selected from H, -NO2, halogen, C1-C6 alkyl with a straight chain, where at least one of R1 and R2 is different from H; m equals 0, 1, 2 or 3; X is selected from a group consisting of: indole of formula (A) bound in position 2, indole of formula (B) bound in position 3 and indazole of formula (C) bound in position 3:

, , ,

where R3 is selected from H and C1-C6 alkyl with a straight chain; R4, R5, R6 and R7 are independently selected from H and C1-C6 alkoxy group; R8 is selected from H and C1-C6 alkyl, or any of its pharmaceutically acceptable salts to obtain a medicinal agent for treating or preventing diseases or conditions mediated by GSK-3, especially neurodegenerative diseases such as Alzheimer's disease or insulin-independent sugar diabetes. The invention also relates to a compound of formula (I), a pharmaceutical composition based on said compound and synthesis method thereof.

EFFECT: high efficiency of using said derivatives.

30 cl, 3 tbl, 7 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel compounds of formula I or pharmaceutically acceptable salts thereof, which have receptor tyrosine kinase type I inhibiting properties and can be used in treating hyperproliferative disorders in mammals. In general formula

,

A is O or S; G is N; B is a 6-member aryl or 5-6-member heteroaryl ring containing a sulphur atom as a heteroatom; E is

, , , , , X is N or CH; D1, D2 and D3 independently denote N or CR19; D4 and D5 independently denote N or CR19 and D6 is O, S or NR20, where at least one of D4 and D5 is CR19; D7, D8, D9 and D10 independently denote N or CR19, where at least one of D7, D8, D9 and D10 is N; R1 is H or C1-C6 alkyl; each R2 independently denotes halogen, cyano, nitro etc, trifluoromethyl, difluoromethyl, fluoromethyl, fluoromethoxy, difluoromethoxy, trifluoromethoxy, azido, -SR18, -OR15, -C(O)R15, -C(O)OR15, -NR14C(O)OR18, -OC(O)R15, -NR14SO2R18, -SO2NR15R14, -NR14C(O)R15, -C(O)NR15R14, -NR15C(O)NR15R14, -NR13C(NCN)NR15R14, -NR15R14, C1-C12alkyl, C2-C12 alkenyl, alkynyl, saturated or partially unsaturated C3-C10cycloalkyl, C3-C10cycloalkyl-C1-C12alkyl, -S(O)p(C1-C6alkyl), -S(O)p(CR13R14)q-phenyl, phenyl, phenyl-C1-3-alkyl, 5-6-member heteroaryl, 5-6-member heteroaryl-C1-C3-alkyl, saturated or partially unsaturated 3-8-member heterocyclyl, 5-6-member heterocyclyl-C1-C3-alkyl, -O(CR13R14)q-phenyl, NR15(CR13R14)q-phenyl, O(CR13R14)q-(5-6-member heteroaryl), NR13(CR13R14)q-(5-6-member heteroaryl, -O(CR13R14)q-(3-8-member heterocyclyl) or -NR15(CR13R14)q-3-8-member heterocyclyl), each R3 denotes Z, where Z is selected from and , W is O or S; W2 is O or S;V is CR8R9, R8b is H or C1-C6alkyl; each of R6, R8, R8a and R9 independently denotes hydrogen, trifluoromethyl, C1-C12alkyl etc.

EFFECT: improved properties and high efficiency of using the compounds.

25 cl, 13 dwg, 1 tbl, 36 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel diarylamine-containing compounds of formula (I) or formula (4b), pharmaceutically acceptable salts thereof, which have c-kit inhibiting properties. In formulae (I) and (4b), each R1 independently denotes H, -C(O)OH and -L1-C1-6alkyl, where L1 denotes -O- or -C(O)O-, or any two neighbouring R1 groups can together form a 5-6-member heterocyclic ring containing a nitrogen atom or an oxygen atom as a heteroatom, a 6-member heterocyclic ring with one or two nitrogen atom s as heteroatoms, optionally substituted with a C1-4alkyl, and R5 denotes hydrogen or C1-C6alkyl; values of radicals Ar and Q are given in the claim. The invention also relates to a pharmaceutical composition containing said compounds, and a method of treating diseases whose development is promoted by c-kit receptor activity.

EFFECT: more effective use of the compounds.

17 cl, 3 tbl, 9 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to a compound of formula in which R1 means hydrogen or alkyl with 1-4 carbon atoms, R2 means hydrogen and L means an alkandiyl group with 1-4 carbon atoms, one CH2-group in which can be substituted by with oxygen atom or a group of formula: or in which * means a conjunction with nitrogen atom, R3 means hydrogen, methyl, propane-2-yl, propane-1-yl, imidazol-4-ylmethyl, hydroxymethryl or 4-aminobutan-4-yl, or R3 is connected with R1 together with which forms (CH2)3- or (CH2)4- -group, R4 means hydrogen or methyl, R5 means alkyl with 1-4 carbon atoms, and R6 means hydrogen or alkyl with 1-4 carbon atoms, and also to its salt and to a method of preparing it.

EFFECT: there are prepared new compounds which can find application in medicine for treating and/or preventing diseases, first of all thromboembolic diseases.

5 cl, 4 tbl, 23 ex

FIELD: chemistry.

SUBSTANCE: described are novel derivatives of azabicyclo{3,1,0}hexane of general formula (I) or pharmaceutically acceptable salts thereof (values of radicals are given in the claim), synthesis method thereof, intermediate compounds, a pharmaceutical composition and use of the novel compounds in therapy as dopamine receptor D3 modulators, for example, for treating drug dependence or as antipsychotic agents.

EFFECT: improved properties of the derivatives.

34 cl, 122 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a compound of formula

in modification 11, characterised by the following spectral data in the near infrared region [cm-1]: 4086, 4228, 4418, 4457, 4634, 4905, 5846, 5911, 6026, 6081, 6582, as well as to the amorphous form of this compound, characterised by the following spectral data in the near infrared region [cm-1]: 4006, 4081, 4224, 4307, 4403, 4634, 4875, 5193, 5865, 6017, 6073, 6696, 7028, 8452, 8873.

EFFECT: novel polymorphous and amorphous form of compounds of formula I is obtained, having high solubility compared to the existing modification.

6 cl, 7 ex, 8 tbl, 9 dwg

FIELD: chemistry.

SUBSTANCE: invention relates to novel compounds of formula I or pharmaceutically acceptable salts thereof, which have receptor tyrosine kinase type I inhibiting properties and can be used in treating hyperproliferative disorders in mammals. In general formula

,

A is O or S; G is N; B is a 6-member aryl or 5-6-member heteroaryl ring containing a sulphur atom as a heteroatom; E is

, , , , , X is N or CH; D1, D2 and D3 independently denote N or CR19; D4 and D5 independently denote N or CR19 and D6 is O, S or NR20, where at least one of D4 and D5 is CR19; D7, D8, D9 and D10 independently denote N or CR19, where at least one of D7, D8, D9 and D10 is N; R1 is H or C1-C6 alkyl; each R2 independently denotes halogen, cyano, nitro etc, trifluoromethyl, difluoromethyl, fluoromethyl, fluoromethoxy, difluoromethoxy, trifluoromethoxy, azido, -SR18, -OR15, -C(O)R15, -C(O)OR15, -NR14C(O)OR18, -OC(O)R15, -NR14SO2R18, -SO2NR15R14, -NR14C(O)R15, -C(O)NR15R14, -NR15C(O)NR15R14, -NR13C(NCN)NR15R14, -NR15R14, C1-C12alkyl, C2-C12 alkenyl, alkynyl, saturated or partially unsaturated C3-C10cycloalkyl, C3-C10cycloalkyl-C1-C12alkyl, -S(O)p(C1-C6alkyl), -S(O)p(CR13R14)q-phenyl, phenyl, phenyl-C1-3-alkyl, 5-6-member heteroaryl, 5-6-member heteroaryl-C1-C3-alkyl, saturated or partially unsaturated 3-8-member heterocyclyl, 5-6-member heterocyclyl-C1-C3-alkyl, -O(CR13R14)q-phenyl, NR15(CR13R14)q-phenyl, O(CR13R14)q-(5-6-member heteroaryl), NR13(CR13R14)q-(5-6-member heteroaryl, -O(CR13R14)q-(3-8-member heterocyclyl) or -NR15(CR13R14)q-3-8-member heterocyclyl), each R3 denotes Z, where Z is selected from and , W is O or S; W2 is O or S;V is CR8R9, R8b is H or C1-C6alkyl; each of R6, R8, R8a and R9 independently denotes hydrogen, trifluoromethyl, C1-C12alkyl etc.

EFFECT: improved properties and high efficiency of using the compounds.

25 cl, 13 dwg, 1 tbl, 36 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel 3,4-dihydrobenzoxazine compounds of general formula [1] (where X denotes a nitrogen atom or CR3; R1 denotes a hydrogen atom or a halogen atom; R2 denotes a C1-6alkoxy group which can be substituted with 1-5 identical or different substitutes selected from a halogen atom and a hydroxyl group; and R3 denotes a halogen atom. However, R1 denotes a halogen atom when X denotes CR3). Said compounds are effective when treating diseases where activity of vanilloid receptors subtype 1 (VR1) is involved, e.g. pain.

EFFECT: more efficient use of pharmaceutical compositions based on said compounds, more effective treatment or pain killing.

19 cl, 4 tbl, 10 ex

FIELD: chemistry.

SUBSTANCE: disclosed compounds have activity and selectivity towards the GABA A receptor subunit α5. In formula I , R1 denotes hydrogen, halogen, phenyl, a 6-member heterocycyl with 2 heteroatoms selected from N, O, a 5-member heteroaryl with 1-2 heteroatoms selected from S, N, cyano, lower alkyl, -(CH2)n-C3-C7-cycloalkyl, -(CH2)n-N(R)2, -(CH2)n-O-lower alkyl or -(CH2)n-OH; equals 0, 1 or 2; R denotes hydrogen or lower alkyl; R2 denotes C3-C7-cycloalkyl, phenyl, 5-6-member heteroaryl with 1 heteroatom selected from N, S or a 9-10-member bicyclic heteroaryl with 1-3 heteroatoms selected from N, which are possibly substituted with one or more substitutes selected from a group comprising halogen, cyano, nitro, oxo group, lower alkyl, lower alkyl substituted with a halogen, lower alkoxy, lower alkoxy substituted with a halogen, -C(O)O-lower alkyl, lower alkylsulphonyl, -NRaRb, -C(O)-NRaRb, -C(O)-(6-member heterocyclyl with 2 heteroatoms selected from N, O), benzyloxy, 6-member heterocyclyl with 1-2 heteroatoms selected from N, S, O, possibly substituted with hydroxy, 1-2 oxo-groups, halogen or lower alkyl, or selected from a 5-6-member heteroaryl with 1-3 heteroatoms selected from N, possibly substituted with lower alkyl; Ra and Rb independently denote hydrogen, lower alkylsulphonyl, -C(O)H, -(CH2)n-N(R)2, -(CH2)n-O-lower alkyl, -(CH2)n-S-lower alkyl, -(CH2)n-S(O)2-lower alkyl, (5-member heteroaryl with 1 heteroatom selected from S)-sulphonyl, lower alkyl, -(CH2)n-(5-6-member heterocyclyl with 1 heteroatom selected from O, N), possibly substituted with lower alkyl, oxo group, or denotes -(CH2)n-C3-C7-cycloalkyl, -(CH2)n-(5-6-member heteroaryl with 1-2 heteroatoms selected from N), possibly substituted with an oxo group, -(CH2)n-OH, -(CO)-R', where R' denotes C3-C7-cycloalkyl, a 5-member heteroaryl with 1 heteroatom selected from S, or lower alkyl; R' denotes a phenyl or a 6-member heteroaryl with 1 heteroatom selected from N which are possibly substituted with a halogen or lower alkyl, optionally substituted with a halogen. The invention also relates to a medicinal agent containing one or more compounds of formula I and use of the disclosed compounds to prepare a medicinal agent.

EFFECT: high effectiveness of derivatives.

16 cl, 145 ex

Iap inhibitors // 2425838

FIELD: chemistry.

SUBSTANCE: invention relates to novel compounds of formula

, which can inhibit binding of protein Smac with apoptosis protein inhibitor (IAP).

EFFECT: improved properties of the inhibitor.

4 cl, 198 ex

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of formula , where R3 has any

of the formulae , where R1 is selected from

,

where each R2 independently denotes hydrogen, halogen, C1-C8alkyl, C1-C8alkoxy- C1-C8alkyl, C1-C8alkoxy; R4 denotes a five- or six-member monocyclic ring system, having two heteroatoms selected from O, N and S, such as pyrazinyl, isoxazole or thiazolyl, each of which can be optionally substituted with one or more of the following substitutes: C1-C8alkyl or C1-C8alkoxy; R5 and R6 independently denote hydrogen or C1-C8alkyl; R7 and R8 together form a cyclopentyl ring; R9 independently denotes C1-C8alkyl; R9a independently denotes C1-C8alkylcarbonyl or phenylcarbonyl; R10 denotes hydrogen; R11 independently denotes C1-C8alkyl or C1-C8alkoxy; R12 denotes hydrogen or -COOR17; R13 independently denotes hydrogen, phenyl and a 6-member heteroaryl containing one heteroatom selected from N; R17 denotes hydrogen; R23 denotes (a) C1-C8alkyl, phenyl, a 5-member heteroaryl containing 1-2 heteroatoms selected from S and N, where any phenyl or heteroaryl residue is optionally substituted with a halogen, C1-C8alkyl or C1-C8alkoxy; R24 denotes C1-C8alkyl; R27 denotes H, C1-C8alkyl, C1-C8alkoxy, O-phenyl, S-phenyl; R29 denotes -(CH2)w-COOR17; where w=0; R31 denotes hydrogen; and pharmaceutically acceptable salts thereof. The invention also relates to a method of producing the disclosed compounds, a pharmaceutical composition, having dual acting ATI and ETA receptor antagonist properties, containing the disclosed compound as an active component, use of the compound in preparing a medicinal agent and methods of treating arterial hypertension.

EFFECT: high effectiveness of the compounds.

8 cl, 1 dwg, 39 ex

Heterocompound // 2425832

FIELD: chemistry.

SUBSTANCE: invention relates to a compound of formula

or pharmaceutically acceptable salt thereof, where symbols assume the following values; ring denotes

or , X denotes a single bond, -CH2-, -NR3-, -O-, -S-, R1 denotes a halogen; phenyl; pyridyl; (C3-C8)cycloalkyl; or (C1-C6) alkyl or (C2-C6) alkenyl, each of which can contain a halogen, -CONH2, phenyl or (C3-C8)cycloalkyl as a substitute, R2 denotes CN, -O-(C1-C6)alkyl, -C(=O)H, halogen; or (C1-C6)alkyl, which can be substituted with a halogen or -OH, R3 can form morpholino or 1-pyrrolidinyl together with R1 and nitrogen, and when X denotes a single bond, R1 and R2 can jointly form a 5-member ring and additionally contain -(C1-C6)alkyl as a substitute, R4 denotes the following ring: , , , , , , , , , , or , where any one of the bonds in the ring is linked to an oxazole ring, R5 denotes -H, (C1-C6)alkyl, which can be substituted by not less than one group selected from: -C(=O)NRXRY, -NHRX and -ORX- (C2-C6)alkenyl-; -C(=O)H; -C(=O)NRXRY, RX and RY can be identical or different and denote -H; or (C1-C6)alkyl. The invention also relates to a pharmaceutical composition based on said compounds, having SlP1 agonist activity.

EFFECT: compounds and compositions can be used in medicine for preventing and treating rejection during organ transplant, bone marrow or tissue transplant and autoimmune diseases.

16 cl, 84 tbl, 198 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel organic compounds of formula where R1 denotes H; halogen; -C0-C7-alkyl-O-R3; -NR4R5; R2 denotes phenyl, substituted with one or two substitutes selected from a group consisting of C1-7alkyl, halogen-C1-7alkyl, C1-7alkoxy, halogen-C1-7alkoxy, phenoxy, halogen, C1-7alkylpiperazinyl-C1-7alkyl, C3-C8-cyclalkyl, C1-7alkylpiperidinyl-C1-7alkyl and C1-7alkylimidazolyl; R3 denotes H or phenyl-lower alkyl; R4 and R5 are independently selected from a group consisting of H; lower alkyl; lower alkoxy-carbonyl and amino; A, B and X are independently selected from C(R7) or N, provided that not more than one or A, B and X denotes N; R7 denotes H; R8 denotes hydrogen; n equals 0; Y denotes O; Z denotes C; W is absent; K denotes N or C, and either a) if K denotes C, the bond shown by a wavy line () is a double bond, Q is selected from O-N, S-N, O-CH and S-CH, where in each case, the left-hand O or S atom is bonded through a bond shown in formula I to K, the right-hand N or carbon (CH) atom is bonded to C through a bond shown by a dotted line () in formula I, provided that said bond, which is shown by the dotted line, is a double bond with C; and the bond shown by a thick line () is a single bond; or b) if K denotes N, the bond shown by a wavy line () is a single bond; Q denotes N=CH, where the left-hand N atom is bonded through a bond shown in formula I to K, the right-hand carbon (CH) atom is bonded to C through a bond shown by a dotted line () in formula I, provided that said bond, which is shown by a dotted line, is a single bond with C; and the bond shown by thick line () is a double bond; or salt thereof (preferably pharmaceutically acceptable salt). The invention also relates to a pharmaceutical composition, having inhibiting action on protein kinase, containing a compound of formula I or salt thereof in an effective amount and at least one pharmaceutically acceptable carrier material.

EFFECT: heterocyclic carboxamides as kinase inhibitors.

12 cl, 25 ex

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